AU690576B2 - Hydroisoquinoline derivatives - Google Patents

Abstract

PCT No. PCT/EP94/02325 Sec. 371 Date Apr. 18, 1996 Sec. 102(e) Date Apr. 18, 1996 PCT Filed Jul. 14, 1994 PCT Pub. No. WO95/04734 PCT Pub. Date Feb. 16, 1995Tricyclic derivatives of octahydroisoquinoline of formula (I), wherein n is zero or 1 and if n is zero, one of X or Y is NH, oxygen or sulphur, and the other is NH, CH or a R4- or R5-substituted carbon atom; if n is 1, then X and Y are both nitrogen, or one of them is nitrogen and the other is CH or an R4- or R5-substituted carbon atom, have selective receptor agonist or antagonist activity, and are of potential therapeutic utility as analgesics or immunomodulating and/or cardiovascular agents. <IMAGE>

Description

I har-^-~ WO 95/04734 PCT/EP94/02325 HYDROISOQUINOLINE DERIVATIVES This invention is concerned with novel hydroisoquinoline derivatives, processes for their preparation, and their use in medicine.

The presence of at least three populations of opioid receptors 8 and kappa) is now well established and documented and all three appear to be present in the central and peripheral nervous system of many species, including man (Lord J.A.H. et al., Nature 1977, 267, 495).

Activation of all 3 opioid receptor subtypes can lead to antinociception in animal models. In particular, studies with peptidic 5 agonists have indicated that activation of the 5 receptor produces antinociceptive activity in rodents and primates, and can induce clinical analgesia in man (Yaksh T.L. and Onofrio, Lancet 1983, 1386). Some experiments suggest that these 5 analgesics may also lack the usual side-effects associated with p and kappa receptor activation (Galligan et at, J.

Pharm. Exp. Ther. 1984, 229, 641).

Octahydroisoquinoline derivatives having selectivity for the 8 receptor have already been described. All the known derivatives are characterized by bicyclic heterocycle systems condensed at the isoquinoline ring. For example, octahydroisoquinoline derivatives are disclosed in EP-A-0,485,636 (Toray Ind.); JP- A-4,368,384, (Toray Ind.), whereas quinoline- and quinoxalineoctahydroisoquinoline derivatives are disclosed in JP-A- 6,275,288 (Toray Ind.). In WO 93/01186 (Dr. Lo Zambeletti), indole-, benzofuro- or quinolinooctahydroisoquinoline derivatives are disclosed.

A structural characteristic of the compounds disclosed in the documents mentioned above, therefore, is the presence of a condensed tetracyclic system.

A novel class of tricyclic derivatives of octahydroisoquinoline condensed with monocyclic heterocycles has now been found, characterised by a selective 6 receptor agonistic or antagonistic activity. These derivatives are therefore of potential therapeutic utility as analgesics or immunomodulating and/or cardiovascular agents.

According to the present invention, there is provided a compound, or solvate or salt thereof, of formula

R,

R

2

R,

N )n R Y R3 0 -1re r IL B~ Il- e~-Y~ WO 95104734 PCTIEP94/02325 wherein: R is hydrogen or a straight or branched CI-C 5 alkyl, C 3

-C

7 cycloalkyl, C 4

-C

6 cycloalkylalkyl, C 3

-C

5 alkenyl, aryl, aralkyl or furan-2-yl-alkyl; Rl and R 2 which can be the same or different, are each hydrogen, hydroxy, Cl-C 3 alkoxy, preferably methoxy, halogen, SH, G 1

-C

4 -alkcylthio, NHR 6

NR

6

R

7

NHCOR

6

NHSQ

2

R

6 wherein R 6 and R 7 which are the same or different, are hydrogen or Cl-C 6 alkyl;

R

3 is hydrogen, hydroxy or Cl-C 3 alkoxy, preferably inethoxy; R4 is a group

R

2 (Rl and R 2 having the meanings defined above) or a -C(Z)-R 8 group, in which Z is oxygen or sulphur, and R 8 is CI-C 18 -alkyl, Cl-C18-alkoxy or NR 9 Rl 0 wherein

R

9 and R 10 which may be the same or different, are hydrogen, straight or branched or, Cl-C 6 ailkyl, C 3

-C

7 cycloalkyl, C 4

:-C

6 cycloalkylalkyl, C 3

-C

6 alkenyl, aryaralkyl orl pilly substitted hctcrccycli riPng or, taken together with the nitrogen atom which they are linked to, they form an alkylene chain having from 2 to 5 carbon atoms, optionally interrupted by an oxygen or nitrogen atom; or R 4 is a groupR1

N-CZ-R

12 in which Rll and R 12 are the same as R 9 and R 10 respectively, and Z is as defined above;

R

5 is hydrogen, C 1

-C

1 8 alkyl, C 2

-C

1 8 alkenyl, trifluoromethyl or is a /i Iq group

R

2 (R I and R 2 having the meanings defined above); n is zero or 1; if n is zero, one of X or Y is NH, oxygen or sulphur, and the other is NH, CH or a

R

4 or R 5 -substituted carbon atom; if n is 1, then X and Y are both nitrogen, or one r IR,14 of them is nitrogen and the other is CH or a R 4 or R 5 -substituted carbon atom.

WO 95/04734 WO 9504734PCT/FEP94OZ32S When R is aryL~ it is preferably phenyl, and when it is aralkyl, it is preferably phenyl-Cl-C6 alkyl.

Examples of R are hydrogen, methyl, ethyl, cyclopropylmethyl, propyl, 2furylmethyl and 2-phenylethyl.

Examiples of RI and R2 are hydrogen, hydroxy, methoxy, chlorine, bromine, fluorine, SHL methylthio, amino, inethylamino, ethylamino, dimethylamino, diethylamino, dilsopropylamino, methylisopropylamino, acetylamino and sulfonylamino, at any position of the ring.

Examples of R 6 and R 7 groups are hydrogen, methyl, ethyl, n-propyl, isopropyl and n-butyl.

Examples of R8 groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, npentyl, n-heptyl, n-undecyl, n-tridecyl, n-heptadecyl, methoxy, ethoxy, propoxy, isopropoxy, hexyloxy, decyloxy, amino, methylainino, dimethylamino, diethylarnino.

Examples of R 4 are ethoxycarbonyl, i-butyloxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-ipropylaminocarbonyl, pyrrolidinocarbonyl, benzylaminocarbonyl, phenylaminocarbonyl, morpholinocarbonyl, N-ethyl-N-i-isopropylaminocarbonyl, diethylaininothiocarbonyl, phenyl.

Examples of R 5 groups are hydrogen, methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, dodecyl, octadecyl, allyl, trifluorornethyl and phenyl.

Examples of R 9 and R 10 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, benzyl, phenyl, pyrrole, furan and pyridine. Examples of the group

R

ill -N-CZ-Rl 2 are ar-etamido, propionamido, isobutyramido and benzamido.

A first group of preferred compounds of formula is one in which n is zero, X is NH and Y is CHi or a R 4 or R 5 -substituted carbon atomn.

A second group of preferred compounds of formula is one in which n is zero, X is CHi or a R 4 or R 5 -substituted carbon atom and Y is NH.L A third group of preferd compounds of formula is one in which n is zero, X is a sulphur or oxygen atom and Y is CHi or a R 4 or R 5 -substituted carbon atom.

A fourth group of preferred compounds of formula is one in which n is zero, X is CH or a R 4 or R 5 -substituted carbon atom, and Y is an oxygen or sulphur atom.

A fifth group of preferred compounds of formula is one in which n is 1, X is a nitrogen atom and Y is Cli or a R 4 or R 5 -substituted carbon atom.

A sixth group of preferred compounds of formula is one in which n is 1, X -3- ~UBBea~s ~r I WO 95/04734 PCT/EP94/02325 is CH or a R 4 or R 5 -substituted carbon atom and Y is a nitrogen atom.

Particularly preferred compounds of formula are those in which R 5 is hydrogen and R 4 is a

Z

II

-C-R

8 group wherein R 8 is a C 1

-C

6 alkyl, C 1

-C

4 alkoxy or -NR 6

R

7 group, R 6 or R 7 being as defined above.

Most preferred compounds are those in which R 8 is a -NR 6

R

7 group and Z is oxygen.

The compounds of formula or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula or its salt or solvate.

One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.

Examples of pharmaceutically acceptable salts of a compound of formula (I) include acid addition salts with the conventional pharmaceutical acid,, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, as;orbic and methanesulphonic acids.

Examples of pharmaceutically acceptable solvates of a compound of formula include hydrates.

The compounds of formula may exist as cis or trans isomers, and the invention extends to both such forms as well as to their single enantiomers and to mixtures thereof, including racemates.

The invention also provides processes for the preparation of the compounds of formula Compounds of formula in which n is zero, X is NH and Y is a substituted carbon atom, are obtained by cyclization of ketones of formula (II) (J.

Org. Chem. 4, 1442 (1989)) with hydrazones of formula (III), working in the presence of metal zinc in acetic buffer, analogously to the method described in Khimiva Geterot. Soed. 342-4, 1972; see scheme 1: L~a LLI 0 I I I I_ WO 95/04734 PCT/EP94/02325 Scheme 1 NH0 N. R 4 O Rs

CH

3

COOH/CH

3 COONa Compounds of formula in which n is zero, X is NH and Y is a R4substituted carbon atom, are obtained by cyclization of bromoketones of formula (IV) (which may be obtained from ketones (II) by reaction with cupric bromide in chloroform, analogously to the method described in J. Og. Chem. 22, 3459 (1964)), with ketones in the presence of ammonia, analogously to the method described in Can.,J. Chem 48, 1689 (1970); see scheme 2: Scheme 2 CuBr 2 SRs R4 NH Compounds of formula in which n is zero, X is oxygen and Y is a R 5 substituted carbon atom, are obtained by cyclization of ketones (II) with ahaloketones (preferably a-chloroketones) in the presence of bases, analogously to the method described in J. Org. Chem. 49, 2317 (1984); see scheme 3: s 9 d l~b -71

L-

WO 95/04734 PCT/EP94/02325 Scheme 3 R4 (il) O c Base

(VI)

Compounds of formula in which n is zero, X is oxygen and Y is a R4substituted carbon atom, are obtained by cyclization of bromoketones (IV) with ketones in ethanol, in the presence of a base (suitably sodium ethoxide) analogously to the method described in J. Chem. Soc. Perkin I, 2372, (1972); see scheme 4: .0 Scheme 4 (IV) 0 R,4 NaOEt/EtOH Compounds of formula in which n is zero, X is sulphur and Y is a substituted carbon atom, are obtained by reacting B-diketones (VII) (which can be prepared by Claisen condensation from ketones (II) and esters of formula R 5 -COOEt; J. Am. Chem, Soc. 2, 1510, 1945) with mercaptans (VIII) in the presence of hydrochloric acid, analogously to the method described in DE 1.088.507 56, 456 (1962)); see scheme Scheme Base (11) 5 Et RsCOOEt

HCI

HS R 4 (Vill) 11_1__ WO 95/04734 PCTIEP94/02325 Compounds of formula in which n is zero, Y is sulphur and X is a R4substituted carbon atom are obtained by reacting ao-mercaptoketones (IX) (which are prepared starting from bromoketones (IV) and H 2 S in potassium hydroxide Am.

Chem. Soc. 107, 4175 (1985)) with acetylene derivatives in aprotic solvents (preferably dimethylsulfoxide) in the presence of bases such as potassium tertbutoxide, as described in Chem, Ber. 2109 (1964); see scheme 6: Scheme 6

H

2 S, KOH (IV)

I

t-BuOK, DMSO 4- Compounds of formula in which n is 1, X is a nitrogen atom and Y is CH are obtained by reacting hydroxymethyleneketones (XI) (which can be prepared from ketones (II) by condensation with ethyl formate in the presence of a base; QrgSynth Coll. Vol. 4, 536, 1963) with enamine (XII), analogously to the method described in Ind. Chem. Soc. 2, 289 (1935); see scheme 7: Scheme 7

()HO

2 Et Base 0

R

R OH

NH

R

R,

R

Compounds of formula in which n is 1 and both X and Y are nitrogen atoms are obtained according to the invention by reacting of a-hydroxyiminoetones (XIII) (which can be prepared by reacting ketones (II) with isoamyl nitrite and potassium tert-butoxide; J. Med. Chem. 34, 1715, 1991) with ethanediamine (XIV) and subsequent aromatization of the intermediate by oxidation in basic medium, analogously to the method described in Chem. Ber. 110, 555 (1967); see scheme 8: -7i WO 95/04734PCIP4025 PME P94/02325 Scheme 8 (I)i-Amylnitrite t-BuOK

NH

2

NH

2

R

4

(XIV)

NaOH R -N,

(XIII)

Compounds of formula in which n 0, X and Y are both N, may be obtained from hydroxyimino derivatives (XV) and RI.- R 5 -substituted chioroimidates of formula (XVI) in basic media, and subsequent treatment of the intermediates with H+ in refluxing toluene Org. C~hem., 52, 7092, (1993)) as described in scheme 9: Scheme 9

NH

2 0H

(HI)-

H l1) TEAN A 2)TsOH, toluene R IN=1N R R 3

(XVI)

(XV)

The compounds of formula in which n is zero, Y is an heteroatomn and X is a R 4 or R 5 -substiruted carbon atom (or in which n is 1, X and Y are both nitrogen atoms and the substituents R 5 and R 4 are reversed) can be obtained according to analogous schemes to those shown above, starting from isomer ketones of formula

N

/41

R

3 (Ha) which can in their turn be obtained according to the method described in L-Med -8oil WO 95/04734 PCT/EP94/02325 Ch 48 (1992).

The processes of the invention also comprise the conversions of substituent groups into other substituent groups, carried out according to per known methods, on the final compounds for example demethylation of methoxy groups to hydroxy groups, or alkylation of the latter or of SH or NH groups, and the like.

As mentioned before, the compounds of formula exist in more than one stereoisomeric form and the process of the invention produces mixtures thereof.

The individual isomers may be obtained from the enantiomerically pure intermediates.

The individual forms of the compounds of formula (i 'say b~ e se arated one from another by resolution using an optically active acid such v, anc acid or 0,0'di-p-toluoyltartaric acid. Alternatively, the single enantiomers can be prepared by an asymmetric synthesis.

The compounds of formula may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.

Solvates of the compounds of formula may be formed by crystallisation or recrysutulisation from the appropriate solvent. For example hydrates may be formed by crystallisation or recrystallisation from aqueous solutions or solutions in organic solvents containing water.

The salts or the solvates of the compounds of formula which are not pharmaceutically acceptable can also be useful as intermediates in the preparation of pharmaceutically acceptable salts or solvates. Therefore, said salts or solvates are also part of this invention.

The activity of compounds of formula in standard tests shows they are of potential therapeutic utility in the treatment of pain, in the prevention of rejection in organ transplants and skin grafts and, generally, for the treatment of pathological conditions which can be treated or alleviated by opioid 5 receptor agonists or antagonists.

Accordingly the present invention also provides a compound of formula or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.

The present invention further provides a pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of pain, for the prevention of the rejection of organ transplants and skin grafts and, generally, for the treatment of pathological conditions -9- I M~ III~U~ III1II(Wl~n* ~DB n~ l~ PIUILPI-- maa~-- -~a~lll a3 (*R1 WO 95/04734 W CTLmP410/O2325 which can be treated or alleviated by opioid 8 receptor agonists or antagonists.

Such a medicament, and a composition of this invention, may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring egent, lubricant or preservative in conventional manner.

These conventional excipients may be employed for example as in the preparation of compositions of known analgesic agents.

Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form suitable for use in the medical or veterinarian fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of pain, as an immunomodulating and/or immunosuppressive agent and, generally, as opioid 5 receptor agonists or antagonists agents.

The suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to adsorbability and the frequency and route of administration.

The compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.

Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.

The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.

Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.

When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk.

~P 411~ rrra I -ra~ l- r- lal 1 IR WO 95/04734 PCT/EP94/02325 Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The ccmposition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.

Liquid compositions for oral administration may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by non-oral route.

In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated, for presentation in an injectable form, in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to make thb solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn, or a solid form or concentrate which can be used to prepare an injectable formulation.

As mentioned earlier, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 45(\ or 500 mg. The composition may be administered once or more times a day, for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiple doses, if desired, to give the above mentioned daily dose.

No anacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.

11i I sPI ea(e rPII 'Isl~L~WI~A WO 95/04734 WOT X 14)3 4CI 0,23O25 The present invention also provides a method for the treatment and/or prophylaxis of pain and of rejection of transplants and skin grafts in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formula or a pharmaceutically acceptable salt or solvate thereof.

Compounds of this invention atrd their preparation are illustrated in the following Examples, the preparation of intermediates being illustrated in the Preparations.

-12s~ -B I IIR r, WO 99/04734 PCT/EP94/02325 PREPARATION 1 N,N-Diethyl-3-oxobutyramide g (0.31 mol) of ethyl acetoacetate and 24 g (0.33 mol) of diethylamine were stirred in a Parr apparatus at 150 °C for 10'. The crude mixture was distilled at 115- 120 0 C 9 mmHg, to give 32 g of the title compound.

C

8

H

15 N0 2 -1 IR (neat): 2980, 1725, 1640, 1590 cmn- N.M.R. 80 MHz (CDC 3 8 3.6-3.1 6H); 2.2 3H), 1.1 (dt, 6H).

PREPARATION 2 N,N-Diethyl-2-phenylhydrazono-3-oxobutyramide 15.7 g (0.1 mol) of N,N-diethyl-3-oxobutyramide were mixed with 12 g (0.14 mol) of CH 3 COONa, 20 ml of water and 75 ml of ethanol. The solution obtained was cooled to 10 OC and 0.1 rnol of freshly prepared solution of phenyldiazonium chloride [Organic Reactions, R. Adams Ed; Wiley, New York, 10, 32-33, (1951-1959)] were added dropwise. The precipitated solid was filtered, dried in vacuo yielding 22.6 g of the title compound. M.p. 63-65 oC.

C

1 4H 19

N

3 0 2 IR (neat): 2970, 1720, 1620, 1605, 1560, 1245 cm- 1 N.M.R. 300 MHz (CDCl 3 8 9.3 1H); 7.4-7.2 5H); 3.6 2H); 3.2 2H); 3H); 1.35 3H); 1.2 3H).

MS (TSP) m/z 262.1 (MH+) PREPARATION 3 N,N-Dipropyl-3-oxobutyramide 43.4 g (43.3 mol) of ethyl acetoacetate and 33.7 g (43.3 mol) of dipropylamine were treated as described in preparation 1. The crude oil was distilled at 86-89 oC 0.8 mmHg, to give 44.3 g of the title compound.

C

10 H1 9 NO2 (neat): 2980, 1725, 1640, 1590 cm-'l N.M.R. 80 MHz (CDC13): 8 3.45 2H), 3.4-2.9 4H), 2.3 3H), 1.7-1.2 (m, 4H), 0.9-0.6 6H).

MS (TSP) m/z 186.3 (MH -13- ~a I C~CI WO 95/04734 WO !~SIO474 1'MI.MP4023,25 PREPARATION 4 N,N-Dipropyl-2-phenylhydrazono-3-oxobutyramide 18.5 g (0.1 mol) of N,N-dipropyl-3-oxobutyraxnide,,12 g (0.146 mol) of

CH

3 COONa, 20 ml of water, 75 ml of ethanol and a solution of 0.1 mol of phenyldiazonium chloride were treated as described in preparation 2. The precipitated solid was filtered and dried in vacuo yielding 4.2 g of the title compound. M.p. 79- 0

C.

C

16

H

2 3

N

3 0 2 I.R. (KBr): 2970, 1670, 1610, 1495 cm- 1 N.M.R. 300 MfHz (CDC1 3 8 7.3 1H), 7.4-7.0 (mn, 5H1), 3.5-3.1 (st, 411), 2.5 (s, 3H), 1.75-1.5 (mn, 4H), 1.0 3H), 0.75 3H1).

MS (TSP) zn/z 290.4 (MH+) PREPARATION i-Butyl acetoacetate ml of ethyl acetoacetate were dissolved in 350 ml of i-butyl alcohol and a catalytic amount of p-toluensulphonic acid (PTSA) was added. The solution was refluxed for 18 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in ether. The resulted solution was treated with s.s. NaHCO 3 The organic layer was separated, dried over Na 2

SO

4 and evaporated in vacuo. The crude oil was distilled at 66-68 IC 4 mnmHg, to give 18.8 g of the title compound.

C

8

H

14 0 3 MS (TSP) ni/z 159.3 M) PREPARATION 6 i-Butyl 2-phenylhydrazono-3-oxobutyrate 15.8 g 1 inol) of i-butyl aceto acetate, 12 g 146 mol) of CH 3 COONa, 20 ml of water, 75 ml of ethanol and a solution of 0. 1 inol of phenyldiazonium chloride were treated as described in preparation 2. The precipitated solid was filtered an dried in vaciso yielding 23.1 g of the title compound. M.p. 45-50 'C.

C1 4 1 1 8

N

2 0 3 I.R. 2970, 1690, 1600, 1530 cin 1 N.M.R. 300 MHz (CDCl 3 8 10-9.2 (bs, 111), 7.4-7.1 (in, 5H1), 4.1 411), 2.5 311), 1.75-1.5 (in, 411), 1.0 311), 0.75 (t, 3H1).

MS (TSP) nx/z 263.3 (MH1I) -14- WO 95/047.14 C'Ii9I2$ 1'CT[9F94/0232$ PREPARATION 7 N-Benzyl-3-oxobutyramide 9 ml (0.05 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene-acetone adduct) were added dropwisge to a solution of 5.5 ml (0.05 inol) of benzylaniine in 20 ml of toluene and the temperature was allowed to rise 70 The solution vvas refluxed for 2 h then the solvent was removed in vacuo. The crude product was titurated with ether obtaining 7.5 g of the title compound. M.p. 84-86 'C.

C

1 1

H

13 N0 2 I.R. (KBr): 3250, 3080, 1720, 1645 cm- I PREPARATION 8 N-Benzyl-2-phenylhydrazono-3-oxobutyraniide 7.27 g (0.038) of N-benzyl-3-oxobutyramide were dissolved in a solution of 5.32 g (0.133 inol) of NaOH in 58 ml of water. To the ice-cooled stirred solution, 0.040 mol of phenyldiazonium chloride were added dropwise at such a rate as to keep the temperature at 0 The precipitated solid was filtered and recrystallised from MeOH yielding 9 g of the title compour~l. M.p. =10 1-103 'C.

C

17 H1 17

N

3

O

2 L.R. (KBr): 3300, 1650, 1510, 1245 cm- 1 PREPARATION 9 1-(3-Oxobutyryl)pyrrolidine 9 ml (0.05 mol) of diketene-acetone adduct and a solution of 4.2 ml (0.05 mol) of pyrrolidine in 20 ml of toluen%. were treated as described in preparation 7. The solvent was removed in vacuo and the residue wias purified by chromatography on silica gel (EtOAc/MeOH 1 yielding 7.6 g of the title compound as a dark oil.

C

8 H1 13 N0 2 I.R. (neat): 29 80, 28 80, 1725, 1645 cm- 1 MS (TSP) m/z 156 (MH+) PREPARATION 1-(2-Phenylhydrazono-3-oxobutyryl)pyrrolidine 7.6 g (0.049 mol) of 1-(3-oxobutyryl)pyr-rolidine, a solution of 6.86 g (0.17 ml) of NaOH in 75 ml of water and 0.05 1 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by 15 f WO 95/04734 WO ~5I4734 Cr/EV94/0232$ chromatography on silica gel PE 2 O) obtaining 8 g of the title compounC; which was used as such in the subsequent step.

PREPARATION 11 N-Phenyl-2-phenylhydrazono-3-oxobutyramide g (25.4 mmol) of acetoacetani4lide, a solution c' 3.46 g (89 inmol) of NaOH in ml of water and 95 minol of phenyidiazonium chloride were treated as described in preparation 8. The residue was crystallised from EtOH, yielding 3.4 g of the title compound. M.p. 96-97 *C.

C

16

H

15

N

3 0 2 I.R. (KBr): 3080, 1675, 1600, 1520 cm MS (TSP) m/z 282.2 (MH+) PREPARATION 12 N,N-Dimnethyl-3-oxobutyraniide A solution of 9 ml (0.05 mmol) of diketene-acetone adduct in 20 ml of toluene was treated with gaseous dimethylamnine at room temperature until the reaction was complete. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MkOH 0%-4 10%) yielding 7.0 g of the title compound.

C

6 HllN0 2 I.R. (neat): 2940, 1720, 1640 cm- 1 PREPARATION 13 N,N-Dimethyl-2-phenylhydrazono-3-oxobutyranide g (0.035 mol) of N,N-dimethyl-3-oxobutyraxnide, a solution of 4.9 g (0.122 mol) of NaOH in 45 ml of water and 0.037 niol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel (hexane/Et 2 O obtaining 3.5 g of the title compound which was used as such in the subsequent step. M.p. =13 1-133 "C.

C

12

H

1 5

N

3 0 2 I.R. (KBr): 3205, 1720, 1630, 1565 cm- 1 -16li WO 95/04734 PCT[94)1/02325 PREPARATION 14 3-Oxobutyramide A solution of 9 ml (0.05 mmol) of diketene-acetone adduct in 20 ml of toluene was treated with gaseous ammonia as described in preparation 12. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc) yielding 5.0 g of the title compound.

C

4 H7N0 2 I.R. (neat): 3300, 1730, 1640 cm-1 PREPARATION 2-Phenylhydrazono-3-oxobutyramide g (0.049 mol) of 3-oxobutyramide, a solution of 6.9 g (0.171 mol) of NaOH in ml of water and 0.051 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel (EtOAc) obtaining 3 g of the title compound which was used as such in the subsequent step. M.p. 146-147 OC.

C

1 4 0

H

1

N

3 0 2 I.R. (KBr): 3320, 1720, 1520 cm-1 PREPARATION 16 N,N-Diisopropyl-3-oxobutyramide 9 ml (0.05 mol) of diketene-acetone adduct and a solution of 47.0 ml (0.05 mol) of diisopropylamine in 20 ml of toluene were treated as described in preparation 7. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (Et 2 0) yielding 7.0 g of the title compound as a dark oil.

C

1 0H 1 9NO 2 I.R. (neat): 2980, 1725, 1640 cm- 1 PREPARATION 17 N,N-Diisopropyl-2-phenylhydrazono-3-oxobutyramide 7.0 g (0.038 mol) of N,N-diisopropyl-3-oxobutyramide, a solution of 5.3 g (0.133 mol) of NaOH in 58 ml of water and 0.04 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel (hexane/Et20 95:5) obtaining 7.5 g of the title compound which was used as such in the subsequent step. M.p. 143-145 °C.

17- L- s~h--e~ll WO 95/04734 W CTIR94/023Z5

C

1 6H 2 3

N

3 0 2 I.R. (KBr): 3210, 2980, 1650, 1620 cm- 1 PREPARATION 18 Ethyl 2-phenylhydrazono-4,4,4-trifluoro-3-oxobutyrate 7.3 ml (0.05 mol) of ethyl 3-oxo-4,4,4-trifluoroacetoacetate, 6 g (0.073 mol) of

CH

3 COONa, 20 ml of water, 37.5 ml of ethanol and a solution of 0.05 mol of phenyldiazonium chloride were treated as described in preparation 2. The crude product was purified by chromatography on silica gel (hexane/Et 2 0 obtaining 8.65 g of the title compound. M.p. 78-80 'C.

C

12

H

1 1

F

3

N

2 0 3 I.R. (KBr): 1710, 1530 cm-1 N.M.R. 300 Miz (DMSO-d 6 8 12.8 1H), 7.8-7.2 5H), 4.2 2H), 1.5 (t, 3H). MS (EI) m/z 288.0 PREPARATION 19 (±)-trans-4a-(3-Methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride A solution of 1.2 g (4.2 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyi)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline and 1.8 g (12.6 mmol) of proton sponge in 34 ml of 1,2-dichloroethane was treated with 1.4 ml (16.8 mnmol) of vinylchloroformate at 0 oC under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 15 min and then refluxed for 3 h, the solvent was removed in vacuo, the residue was taken up in water and extracted with Et 2 O. The organic layer was washed with 3% HC1, then was dried over Na 2

SO

4 and the solvent was removed in vacuo. The dark residue was dissolved in EtOH, 3 ml of concentrated HC) were added and the solution refluxed for 3 hours. The solvent was removed in vacuo, obtaining 0.88 g of the title compound which was used as such in the subsequent step. M.p. 90 0 C dec..

C

16

H

2 1 N0 2

-HCI

I.R. (KBr): 3400, 2970, 1715, 1600 cm- 1 PREPARATION (±)-trans-2-Cyclopropylmethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8adecahydroisoquinoline hydrochloride 0.88 g :nmol) of (±i)-trans-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a- 18a -pa, a WO 95/04734 WO 95104734 I MY19V4/02325 decahydroisoquinoline hydrochloride, 0.44 g (3,23 mmrol) of cyclopropylmethyl bromide, 0.64 g of potassium carbonate and a catalytical amount of potassium iodide in 15.4 ml of DMF were stirred at 60 'C for 2 h. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (EtOAcIMeOlL/conc.NH 4 OH 90:10:0.8). The solid product was dissolved in acetone and the solution brought to acidic pH with HCl/Et 2 O. The precipitate was filtered, yielding 0.28 g of the title compound. M.p. 78 *C dec.

C

2 0

H

2 7

NO

2 -HCl I.R. (KBr): 3400, 2940, 1715, 1600 cm- N.M.R. 300 MvHz (DMSO-d 6 5 7.4-6.8 (mn, 4H1), 3.8 3H1), 3.6- 1.1 (in, 1611), 0.6 (mn, 2H), 0.4 2H-).

MS (El) m/z =314.2 PREPARATION 21 (±)-tras-2-Diethylaxninocarbonyl-8a-(3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8, 8aoctahydro- 1H-pyrrolo[2,3-g~isoquinoline hydrochloride A solution of 0.6 g (1.42 nirol) of (±)-trans-2-diethylaminocarbonyl-6-ethyl-8a-(3methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a-octahydro- lH-pyr-rolo[2,3-glisoquinoline hydrochloride and 0*6 g (2.483 imol) of proton sponge in 35 M1 of 1 ,2-dichlor-oethane was treated with 0.245 ml (2.48 mmol) of vinyichioroformate and then with conc.

HCl in EtOH as described in preparation 19, obtainin'g 0.36 g of the title compound.

C

2 4

H

3 3

N

3 0 2

*HCI

I.R. (KBr): 3400, 2970, 1755, 1600 cm- PREPARATION 22 (±)-trans-2-Butyl-4a-(3-inethoxyp-henyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8adecahydroisoquinoline 0.71 g (2.55 minol) of (±)-trans-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8adecahydroisoquinoline hydrochloride, 0.37 g (2.68 nimol) of butyl bromide, 0.53 g of potassium carbonate and a catalytical amount of potassium iodide in 15 ml of DMF were reacted as described in preparation 20, yielding 0.2 g of the title compound which was used as such in the subsequent step.

C

2 0

)H

2 9 N0 2 I.R. (neat): 3400, 2930, 1715, 1605 cm- 1 -19- L~aarsiAlx7i~ sffrc~aas~l~sar~l.-.;,,,., WO 95/0473 W CTO4rf/r1941023 PREPARATION 23 (±)-trans-2-Etthyl-hydroxyimino-4a-(3-ethoxyphenyD- 1,2,3,4,4a,5,6,7,8,8adecahydroisoquinoline 0.5 g1.54 mmol) of (±)-trans-2-ethyl-4a-(3-m ethoxyphenyl)-6oxo- 1 ,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.456 g (6.56 mmol) of hydroxylamine hydrochloride and 0.64 g of KHC0 3 in 10 il of MeOH were refluxed for 45 min. The precipitate was filtered, the solvent was removed in vacuo and the residue taken up in H20. The pH was adjusted to 8 with conc. NH 4 OH, the aqueous layer was extracted with C11 2 C0 2 The organic layer was dried, the solvent removed in vacuo, obtaining 0.45 g of the title compound which was used as such in the subsequent step.

C

1 8 1 26

N

2 0 2 I.R. (KBr): 2940, 2820, 1605, 1580 cm- 1 PREPARATION 24 (±)-trans-2-Diisopropylaninocarbonyl-8a-(3-methoxy-henyl)-3-methyl- 4,4a,5,6,7,8,8a-octahydro-1H-pyrrolo[2,3-g isoquinoline hydrochloride A solution of 0.57 g (1.26 mmol) of (±)-tranis-2-diisopropylaiocarbonyl-6-ethyl- 8a-(3-miethoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a-octahydro- 11-pyrroloE2,3glisquinoline and 0.54 g (4.52 mmol) of proton sponge in 35 ml of 1,2, dichioroethane was treated with 0.77 ml (4.52 nnol) of vinyl chioroformate and then with conc. HCl in E1OH as described in preparation 19, obtaining 0.34 g of the title compound.

C

2 6H 37

N

3

O

2 *HCl I.R. (KBr): 3400, 2970, 1755, 1600 cm- 1 P L J r M WO 95/04734 PCTI84/02325 EXAMPLE 1 (±)-trans-2-Diethylaminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a-octahydro- 1H-pyrro[2,3-gjisoquinoline 1.6 g (4.9 mmnol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride Med. Chem., 54, 1442, 1989) and 1.54 g (5.8 mmol) of N,N-diethyl-2-phenylhydrazono-3-oxobutyramide were dissolved in a mixture of 5 ml of glacial acetic acid and 0.48 g (5.8 mmnol) of

CH

3 COONa. The solution was heated to 60 OC then, under N 2 atmosphere, 1.47 g (22.5 mmol) of zinc dust were added portionwise. The resulting mixture was refluxed for 2 h and cooled to room temperature. The precipitate was removed by decantation and washed with 5 ml of glacial acetic acid. The combined acidic solutions were diluted with iced water (50 ml), the pH was adjusted to 8 with 20% NaOH and then extracted with AcOEt. The organic layer was dried over Na 2 SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography (AcOEt/MeOH/conc. NH40H 90:10:1; Rf 0.25), yielding 1.4 g of the title compound. M.p. (HCI salt) 247 C dec.

C

2 6

H

3 7

N

3 0 2 I.R. (KBr) 3410, 3200, 2920, 2500, 1600, 1580 cm- 1 N.M.R. 80 MHz (CDCl 3 5 7.3 1H), 7.2-6.6 4H), 3.7 3H), 3.6-2.0 (m, 1.95 1.2-0.9 6H).

MS (TSP) m/z 424.2 (MH+) EXAMPLE 2 (±)-trans-2-Diethylaminocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-glisoquinoline To a solution of 1.89 ml (20.2 mmnol) of boron tribromide in 40 ml of dry CHCl 3 1.43 g (3.37 mmol) of (±)-trans-2-diethylaminocarbonyl-6-ethyl-8a-(3methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3g] isoquinoline dissolved in 15 ml of dry CHCl 3 were added, under N 2 atmosphere, at room temperature. After 2 h the mixture was poured in 200 g of ice containing 20 ml of conc. NH 4 0H. The organic layer was separated, dried over Na 2 SO4 and the solvent removed in vacuo. The residue was purified by flash chromatography (AcOEt/MeOH/conc. NH 4 0H 80:20:2), obtaining 0.8 g of the title compound. M.p. 221-223 OC

C

2 5

H

3 5

N

3 0 2 I.R. (KBr): 3500, 2940, 1575, 1300 cm- 1 N.M.R. 300 MHz (DMSO-d6): 8 10.25 1H), 8.55 1H), 7.0-6.8 3H), 6.45 -21- P1 991~---9 lqpllR rq I L l ~plP IIIRlrB~A~*l~*Zllmrrrrrwrm~n~ WO 95/04734 ramP11,4410=$lU~O 2.85-1.85 201), 1.95 311), 1,0 (dt, 6FI).

MS (TSP) nz 410.2 (MFI+) EXAMPLE 3 (±)-13ans--Ethyl-2-ethoxycarbonyl-3-methyl- 8a-(3-methocyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro- 11-pyrrolo[2,3-gJisoquinoline 0.8 g (2.47 mmol) of (±)-trans-2-ethl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,,4a,,6,7,8,8a-decahydroisoquinoline hydrochloride and 0.87 g (93.7 mmol) of ethyl 2-phenylhydrazono-3-oxobutyrate [Organic Reactions, R. Adams Ed; Wiley, New York, 10, 32-33, (1951-1959)] were dissolved in a mixture of 3 ml of glacial acetic -cid and 0.34 g (4.2 mnol) of CH1 3 COONa. The solution was treated as described in example I adding 0.74 g (11.3 mmol) of zinc dust. The residue was purified by flash chromatography (AcOEtr/Me0IVconc. NH 4 0H 94:5:0.5; Rf 0.3), obtaining 0.6 g of the title compound.

C

2 4 11 32

N

2 0 3 I.R. (KBr): 3300, 2915, 1680, 1600, 1445 cm- N.M.R 300 MHz (DMSO-d6): 8 10.8 1H), 7.2-6.6 4H), 4.1 211), 3.65 (s, 311), 3.1-2.2 (in, 111), 2.1 311), 1.7 2H), 1.1(t, 31), 0.95 311).

MS (TSP) m/z 397.2 (MII+) EXAMPLE 4 (±)-trans-6-Ethyl-2-ethoxycarbonyl-8a-(3-hydroxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-gisoquinoline 0.6 g (1.5 minol) of (±)-trans-6-ethyl-2* zIthoxycarbonyl-3-methyl-8a-(3methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g isoquinoline were treated with 0.84 ml (9.0 mnol) of boron tribromicZ as described in example 2. The crude solid was purified by flash chromatography (AcOEt/MeOH/conc. Nfl 4 0H 80:20:2), yielding 0.12 g of the title compound. M.p. 195 -197 C

C

2 3

H

30

N

2 0 3 I.R. (KBr): 3300,2920, 1690, 1440 cm- 1 N.M.R. 300 M.1z (DMSO-d6): 8 10.8 11), 9.1 1H), 7.1-6.4 311), 4.1 (q, 211), 3.45-1.75 14H), 2.1 31), 1.2 311), 1.0 311).

MS (TSP) m/z 383.1 (M.11) -22- ~I CI F~n~ ar~R la~ sa~l rr~R~I~ WO 95/047,34 wCTIVi71 1 94104/2O2 .2 EXAMPLE3 (±)-ans-Dipropylacmi~ mrbony-6ethiyl3-nethyb 8a(3-meth oxypjhenyl)- 4,4a,5,6,7,8,8a,9-octahydro-. 1pyrrolo(2,3-g$isoquitnoline hydrochloride 0,7 g (2,16 mniol) of (.t)trans-2-hyl-4a-( -rnethoxyphenyl)-6-oxo- 1,2,3,44a,5,6,7,8,8a-decahydroisoquiioline hydrochloride, 0,62 g (2,16 mnmol) of N,Ndipropyl-2-phenylhydrazono-3-oxobtyramide, 0.21 g (2.6 mmol) of

CH

3 COONa, 0.65 g (10 mmol) of zinc dust and 2.5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (AcOEt/Meli/conc, NH40H 90:10:1.5; Rf dissolved in Et2O and the solution brought to acidic pH with HCIIEt 2 O. The precipitate was filtered and recrystallised from a. mixture of AcOEt/Acetone 9/1, yielding 0.65 g of the title compound.

M.p. 250 'C dec.

C

2 8H4 1

N

3 2

HCI

I.R. 3400, 3210,2970, 1600,1580 cnr 1 N.M.R. 300 MHz (DC1 3 8 12 (bs, IH), 8.5 11), 7.4-6.6 (in, 4H), 3.8-2.5 (in, 17H), 2.0 3H), 1.8-1.3 10H), 0.9 6H]).

MS (TSP) n/z (free base)= 452.7 (MH+) EXAMPLE 6 (±)-trans-Dipropylaminocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3-ethyl- 4,4a,5,6,7,8,8a,9-octahydro-l H-py-rrolo[2,3-g]isoquinoline 0.56 g (1.15 mmol) of (±)-ans-dipropylaminocarbonyl-6-ethyl-3-meih.y1-8a-(3methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoquinoline hydrochloride were treated with 0.65 ml (7 nnol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (AcOEt/MeON/conc.

NH

4 0H 75:25:2.5). The crude product was crystallised from acetone yielding 0.075 g of the title compound. M.p. 151-153 *C.

C

27

H

3 9

N

3 0 2 I.R. (KBr): 3150, 2970, 1590, 1450 cm-l N.M.R. 300 MHz (DMSO-d 6 8 10.2 1H), 9.1 1H), 7.2-6.4 (in, 4H), 3.5-1.8 17H), 1.9 3H), 1.6-1.4 4H), 1.0 3H), 0.8 6H).

MS (TSP) m/z 438.4 (MH+) -23pq~ I WO 95/04734~l~ PCO 1(IX 94 /02325 E3XAMPLE 7 (±)-trans-2- (i-Dutoxycarbonyl)-6-ethyl-3-xnethyl-8a-(3-methoxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro-I lB-pyrrolo[2,3-gJ isoquinoline hydrochloride 0.7 g (2.16 mmol) of (±)-tra,,is-2-ethyl-4,-(3- thoxyphenyl)-6-jxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.56 g (2.16 mmol) of ibutyl 2-phenylhydrazono-3-oxobutyrate, 0.21 g (2.6 rmol) of CH 3 COGNa, 0.65 g inol) of zinc dust and 2.5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (AcOEt/MeOH/conc.

NH

4 0H 90:10:1.5; Rf 0.27). The purified free base was dissolved in AcOEt and the solution brought to acidic pH vith WCI/Et 2 O. The precipitate was filtered, washed and dried, to yield 0.56 g of the title compound. M.p. 230 'C dec.

C

2 6

H

3 6

N

2 0 3

HCI

I.R. (KBr): 3400, 2970, 1670, 1600 cm 1 N.M.R. 300 MHz (CDCl 3 5 9.7 1H), 8.4 1H), 7.3-6.6 (mn, 4H), 4.0 2H), 3.8 3H), 3.6-2.5 13H), 2.2 3H), 2.1-1.4 4W), 1.0 6H).

EXAMPLE 8 (±)-trans-2-(i-Butoxycarbonyi)-6-ethyl-8a-(3-hydroxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinoline hydrochloride 0.56 g of (±)-trans-2-(i-butoxycarbonyl)-6-ethyl-3-methyl-8a-(3-nioxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro-H 1-pyrrolo[2,3-glisoquinoline hydrochloride were treated with 0.68 ml (7.26 imol) of boron tribroiide as described in example 2. The residue was purified by flash chromatography (AcOEt/MIeOH/conc. NH 4 0H 75:25:2.5) and then crystallised from AcOEt yielding 0.1 g of the title compound.

M.p. 196-198 0

T

C

2 5

H

3 4

N

2 0- 3 I.R. (KBr): 2960, 1620, 1580, 1320 cm- N.M.R 300 MHz (DMSO-d 6 8 9.2 1H), 8.5 1W), 7.0-6.2 4H), 3.8 (d, 2H), 3.0-1,8 14H), 2.1 3W), 1.1-0.9 9H).

MS (TSP) m/z 41L (MR+) EXAMPLE 9 (±)-trans-2-Diethylaninocarbony.-3,6-dimethyl-8a-(3-inethoxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydfro- 1-pyrrolo[2,3-glisoquinoline 3 g (9.3 rnol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7 ,8,8a-decahydroisoquinoline hydrochloride, 2.92 g (11.2 Inmol) of -24- Y I-~IC- J~q_ n ~earrrpunsaraarana~ suramaa~nnrle~aRanrar WO 98/041.347c~ W /0PCT/UPIOZ$/23 NN-Jiethyl-2-phenylhydazono-3-oxobutyrarnide, 0,92 g (112 inmol) of CH3C000Na, 2.8 g (42.8 niol) of zinc dust and 9.3 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (AcOEt/MeOFconc. NH 4 0H 90:101; Rf 0.27) yielding 0.56 g of the tide compound. M.p. (-101) 250 *C dec.

3 5

N

3 0 2 I.R. (KBr) (hydrochloride): 3410, 3200, 2915, 2510, 1605, 1580 c- 1.

EXAMPLE (±:)-trans-2-Diethylaininoarbonyl-3,6-dimethyl-8a-(3-hydroxyphenyl)- 4,4a,5,67,8,8a,9-octahydro-1H-pyrrolo2,3-g]isoquinoline hydrochloride g (1.22 mmol) of rans-2-diethylainocarbonyl-3,6-dimethyl-8a-.t,3metho~xyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-p rolo[3-g isoquino'line were treated with 0.68 ml (7.2u iMmol) of boron tribrovide as described in example 2. The residue was purfied by flash chromatography (AcOEt/MeOH/conc. NH 4 0H 75-:25:2.5). The crude producl, was dissolved in MeOW and the solution brought to acidic pH with HCIEt 2 Q. The solvent was evaporated in vacuo and the solid crystallised from a mixture of acetone/MeOW 1:1, yielding 0.06 g of the title compound. M.p. >25000C

C

24

H

3 3

N

3 0 2 *HCl IR. (KIBr): 3450, 3120.2970, 1600, 1580 cnr 1 N.M.R. 300 Mz (DMSO-d 6 8 10.4 1H), 9.2 1H), 7.2-6.5 4H), 3.5-2.0 15H), 2.8 3W), 1.9 3W), 1.0 6H).

MS (TSP) n/z(free base) 396.4 (MH+) EXAMPLE 11 (±)..tras-2-Diethylainocarbonyl-3,7-dinethyl-4a-(3-iethoxyphenyl)- 4,4a,5,6,7,R,8a,9-octahydro- 1-pyrrolo[3,2-glisoquinoline 0.9 g (2.9 imol) of (±)-ans-2-ethyl-4a-(3-inethoxyphenyl)-7-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride Med. Chgem., 35, 48, 1992), 0.9 g (3.5 mmol) of N,N-diethyl-2-phenylhydrazono-3-oxobutyramide, 0.28 g minol) of CH 3 CONa, 0.87 g (13.3 mmmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (CW 2

CI

2 /MeOH/conc. NHO0H 86:10:0.6; Rf 0.27), to yield 0.2 g of the title compound. M.p. 153-155 00 dec.

C

2 5

H

35

N

3 0 2 LR. ,KBr): 3250, 2920, 1605,1580 cm 1 25 mr e ~PI WO 95/04734 WO 95/4734 CTlEP14/04325 N.M.R. 300 Mhfz (CDCI 3 8 8.2 1W), 7.1-6.6 (in, 4W), 3.7 3H), 3.6-1.95 (mn, 2.3 3H), 1.9 3H), 1.i 6H).

MS (TSP) m/z 410.5 (MH+) EXAMPLE 12 (±)-trans-2-Diethylaxnirocarbonyl-3,7-dimeth i'4a-(3-hydroxyphenyi)- 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrroloL. 2-1squn n 0.29 g (0.71 inmol) of (±)-rns-2-diethylaminocarbonyl-3,7-dimethyl-4a-(3methc'xyphenyl)-4,4a,5,6,7,8,8a,9-octahydro- 1W-pyrrolo[3,2-g] isoquinoline were treated. with 0.4 ml (4.26 mmiol) of boron tribromide as described in example 2. The residue was purified by flash chromatogrnphy (CH2Ci 2 f1\eOFlconc. NiEL 4

OW

12:0. The crude product was triturated with a mixture of acetone/MeOW 3:2, yielding 0. 14 g of the title compound. M.p. 235-23 8 *C

C

2 4

H

33

N

3 0 2 I.R. (KBr): 3215, 2920, 1610, 1510 cm- N.M.R 300 M~z (DMSO-d 6 5 10.4 1H), 9.1 1H), 7.0-6.4 (mn, 4W), 3.4-2.0 (in, 15W), 2.2 3W), 1.9 3H), 1.0 6W).

MS (TSP) in/z 396.4 (MH+) EXAMPLE 13 (±)-trans-2-Benzylaminocarbonyl-3,6-diinethyl-8a-(3-inethoxyphenyl)- 4,4a 1 5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-gjisoquinoline 1 g (3.3 inmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,Sa-decahydroisoquinoline hydrochloride, 2.95 g (10 minol) of Nbenzyl-2..phenylhydrazono-3-oxobutyraxnide, 0.82 g (10 imol) Of CW 3 COONa, 2.6 g (40 minol) of zinc dust and 5 mil of glacial acetic acid were treated as described in example 1. The residue was crystallised from AcOEt yielding 0.65 g of the title compound. M.p. 162-164 *C

C

2 8 1-1 3 3

N

3 0 2 L.R. 3350, 3220, 2920, 1640, 1630, 1510 cm- 1 EXAMPLE 14 (±)-tans-2-Benzylaninocarbonyl-3,6-diinethyl-8a-(3-hydroxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro-1W-pyrrolo[2,3-glisoquinoline hydrochloride 0.38 g of (±)-trans-2-benzylainnocarbonyl-3,6-dimethyl-8a-(3-methoxyphenyl)- 26 rprr~rc-~- WO 95/04734 11CIVAN/0230225 4,4a,5,6,7,8,8a,9-octahydro- 1I-pyro)u[2,3-g)isoquinoline were treated with 0.55 ml (5.7 mnol) of boron tribromide as described in example 2. The residue was dissolved in MeOH and the solution brought to acidic pH with HCl/Et 2 0. The solvent was evaporated in vacuo and the solid crystallised from a mixture of acetone/MeOH 1:1, yielding 0.15 g of the title compound. M.p. 297-299 'C

C

27

H

3

N

3 0 2

*HCI

I.R. (KBr): 3290, 2910, 1650, 1540, 1320 cm- 1 EXAMPLE (±)-trans-3,6-Dimethyl-8a-(3-methoxyphenyl)-2-pyrrolidinocarbonyl- 4,4a,5,6,7,8,Sa,9-octahydro 1H-pyrrolo[2,3-gjisoquinoline 1 g (3.3 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 2.6 g (10 mmnol) of 1-(2phenylhydrazono-3-oxobutyryl)pyrrolidine, 0.82 g (10 mmol) of CH 3 COONa, 2.6 g mmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by chromatography on silica gel (EtOAc/MeQE then crystallised from a mixture of acetonefMeOH 1:1 yielding 0.65 g of the title compound. M.p. 171-173 *C.

C

2 5

H

33

N

3 0 2 I.R. (KGr): 3280, 2940, 1610, 1580 cm-1.

EXAMPLE 16 (±)-trans-3,6-Dimethyl-8a-(3-hydroxyphenyl)-2-pyrrolidinocarbonyl- 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline hydrochloride 0.38 g of (±)-trans-3,6-dimethyl-8a-(3-methoxyphenyl)-2-pyrrolidinocarbonyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoquinoline were treated with 0.55 ml (5.7 mmol) of boron tribromide as described in example 2. The residue was triturated in Et 2 O and the solution brought to acidic pH with HCIIEt 2 O. The solvent was evaporated in vacuo and the solid crystallised from a mixture of acetonelMeOH 1:1, yielding 0.15 g of the title compound. M.p. 230-233 'C

C

2 4

H

3 jN 3 0 2 -HC1 IR (KBr): 3400, 3140, 1600, 1580, 1510 cm-1 EXAMPLE 17 (±)-trans-6-Ethyl-3-methyl-8a-(3-methoxyphenyl)-2-phenylaminocarbnyl- 4,4a,5,6,7,,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinoline 0.8 g (2.47 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- -27- I I a ~1 s=1 I~sB~Bwl~- l l ri-F11 -m r WO 95/04734~6 WCT(EI /Z10325 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.7 g (2.47 mmol) of Nphenyl-2-phenylhydrazono-3-oxobutyraiide, 0.24 g (3 mnol) of CW 3 COONa, 0.74 g (11.3 nmol) of zinc dust and 2.5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (EtOAc/MeOI-Vconc. NH 4 0H 90: 10: 1) yielding 0.28 g of the title compound. M.p. 178-180 OC.

C

2 8

H

3 3

N

3 0 2 I.R. (KBr): 3280, 2940, 1640, 1590 cm 1 N.M.R. 300 Mhz (CDCI 3 8 7.6-6.6 9H), 3.75 3H), 3.0-2.4 14W), 1.9 (q, 2W), 1.1 3H).

MS (TSP) m/2 444.5 (MH+) EXAMPLE 18 (±)-trans-6-Ethyl-8a-(3-hydroxyphenyl)-3-methyl-2-phenylaminocarbonyl- 4,4a,5,6,7,8,8a,9-octahydro-1W-pyrrolo[2,3-glisoquinoline 0.28 g of (±)-trans-6-ethyl-8a-(3-methoxyphenyl)-3-methyl-2-phenylaminocarbonyl- 4,4a,5,6,7,8,8a,9-actahydro-1H-pyrrolo[2,3-g] isoquinoline were treated with 0.35 ml (1.9 iniol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAcIMeOIL/conc. NH40H 80:20:2) yielding 0.06 g of the title compound. M.p. 271-272 'C.

C

2 7

W

3 lN 3 0 2

WCL

I.R. (KBr): 3310, 294, 1640, 1590 cm- N.MR. 300 MHz (DMSO-d 6 8 10.6 1H), 9.2 (ds, 2H), 7.5-6.4 9H), 3.0-1.9 13H), 2.2 3H), 1.0 3H).

MS (TSP) x/z 430.5 EXAMPLE 19 (±)-trans-2-Diethylaminothiocarbonyl-6-ethyl-3-methyl-8a-(3-methoxyphenyl)- 4,4a,5,6,7,8,8a,9-octalhydro- 1-pyrrolo[2,3-g~isoquinoline 1 g (2.4 minol) of (±)-trans-2-diethylaminocarbonyl-6-ethyl-3-methyl-8a-(3methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1W-pyrrolo[2,3-g]isoquinoline prepared as described in example 1 and 0.48 g (1.2 miol) of Lawesson reagent (Synthesis, 941, 1979) were disiolved in 50 ml of toluene. The solution was refluxed for 6 h. The solvent was evaporated in vaczo. The residue was treated with s.s. K 2 C0 3 and extracted with AcOEt The organic layers were dried over Na 2

SO

4 and then the solvent evaporated in vacuc. The crude product was purified by flash chromatography (AcOEt/MeOH-/conc. NH 4 0H 80:20:2) yielding 0.5 g of the title compound. M.p.

-28- L L- I sl W s~i-I-I WO 95/047-14l W CTft~P94IMN02W 156-158 0

C.

C

2 6H37N 3

OS

LR. (nujol): 1600, 1581, 1461, 1378 cm 1 N.M.R. 300 MHz (CDC1 3 8 8.3 1H), 7.2-6.7 411), 4.0-3.8 411), 3.75 (s, 311), 3.0-1.9 1311), 1.9 3H), 1.2 611), 1.1(t, 3H).

MS (TSP) m/z 440.6 (MH+) EXAMPLE (±)-trans-2-Diethylaninothiocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3-ethyl- 4,4a,5,6,7,8,8a,9-octahydro-l H-pyrrolo[2,3-g]isoquinoline g of (±)-trans-2-diethylaminothiocarbony1-6-ethyl-3-methyl-8a-(3mehoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline were treated with 0.64 ml (6.8 rmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAcIMeOH/conc. NH 4 0H 80:20:2) yielding 0.12 g of the title compound. M.p 243-245 *C.

C

2 5

H

3 5

N

3 0S I.R. (XKBr): 3200, 2900, 1580, 1480 cm- 1 N.M.R. 300 MHz (DMSO-d 6 8 10.2 11), 9.2 11), 7.1-6.4 411), 3.9-3.7 611), 3.0-1.75 1.8 31), 1.1 611), 0.9 31).

MS (TSP) m/z 426.3 (MH+) EXAMPLE 21 (±)-trans-6-Cyclopropylmethyl-2-diethylaminocarbonyl-8a-(3-methoxyphenyl)-3inethyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoquinoline hydrochloride 0.28 g (0.80 minol) of (±)-trans-2-cyclopropylmethyl-4a-(3-iethoxyphenyl)-6-oxo- 1,2,3,4,4a 1 5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.56 g (2.14 ininol) of NN-diethyl-2-phenylhydrazono-3-oxobutyramide, 0.131 g (1.6 mmol) of

CH

3 COONa, 0.402 g (6.16 mmoIl) of zinc dust and 10 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography NH40H 90:10:0.5). The product was dissolved in acetone and the solution brought to acidic pH with Et 2 Q/HCl. The solid was filtered, washed and dried yielding 0.225 g of the title compound. M.p. 190-195 *C.

C

2 8

H

3 9

N

3 0 2 -HCl I.R. (KBr): 3400, 3200, 2915, 2580, 1715, 1600 cm- N.M.R. 300 MHz (DMSO-d 6 8 10.3 (bs, 11), 10.2 1H), 7.3-6.7 41), 3.7 (s, 3H), 3.6-2.5 14H), 2.5 31), 2.1-1.4 41), 1.0 61), 0.6 2H), 0.4 (mn, 211).

-29- _L L CL LII~I-~ C~a m rs~~- WO 51047341 W 4CTIE9IN0232A MS (ET) m/z 450.5 (MH+) EXAMPLE 22 (±)-trans-6-Cyclopropylmethyl-2-diethylaminocarbonyl-8a-(3-hydroxyphenyl)-3methyl-4,4a,5,6,7,8,8a,9-octahydro- 1-pyrrolo[2,3-g] isoquinoline hydrochloride 0.225 g (0.46 mnol) of (±)-trans-6-cyclopropylethyl-2-diethyla.inocarbonyl-8a- (3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro- 1K-pyrrolo[2,3-g) isoquinoline were treated with 0.26 ml (2.76 mmnol) Of boron tribroiide as described in example 2. The residue was purified by flash chromatography

NH

4 0H 75:25:0.5). The crude product was dissolved in acetone and the solution brought to acidic pH with HCJIEt 2 O. The precipitate was filtered yielding 0.07 g sof the tite compound. M.p. 270-272 'C dec.

C

2 7

H

37

N

3 0 2 *HCl I.R. (KBr): 3010, 2700, 1595, 1580 crn 1 N.M.R. 300 MHz (DMSO-d 6 8 10.4 (bs, 1H), 10.3 1H) 9.2 1H), 7.1-6.5 (m, 4H), 3.5-2.0 15H), 2.8 3K), 1.9 3H), 1.0 6H), 0.6 2H), 0.4 2H).

MS (EI) m/z(free base) 435.3 EXAMPLE 23 (±)-trans-2-Diisopropylamninocarbonyl-6-ethyl-8a-(3-mehoxypheny)-3-ethyl- 4,4a,5,6,7,8,8a,9-octahydro- K-pyrrolo[2,3-g) isoquinoline 0.7 g (2.2 mnol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 2.0 g (7.0 iniol) of N,Ndiisopropyl-2-phenylhydrazono-3-oxobutyramide, 0.575 g (7.0 mmol) of

CH

3 COONa, 1.83 g (28.0 rmmol) of zinc dust and 3.5 ml of glacial acetic acid were treated as described in example 1 yielding 1.0 g of the title compound as an oil.

C

2 8

H

4 1

N

3 0 2 I.R. (neat) 3250, 2960, 2580, 1740, 1600 cm- 1 N.M.R. 300 MHz (DMSO-d 6 (hydrochloride): 8 10.2 1K), 7.2-6.6 (in, 4K), 3.7 3K), 3.6-1.8 18K), 1.8 3K), 1.0 12H),.

MS (El) n/z 451.3 EXAMPLE 24 (±t)-rns-2-Diisopropylaminocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3 -methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-gjisoquinoline hydrochloride g (2.2 nnnol) of (±)-trans-2-diisopropylaiinocarbonyl-6-ethyl-8a-(3- ~III I ~8~ WO 95/04734 PeCll/01,P94/0232S methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g) isoquinoline were treated with 1.15 ml (12.0 mmol) of boron tribromide as described in example 2. The crude product was dissolved in MeOH and the solution brought to acidic pH with HC/Et20O. The solvent was evaporated in vacuo and the solid crystallized from acetone, yielding 0.5 g of the title compound. M.p. 263-265 'C

C

2 7

H

3 9

N

3 0 2

HCI

I.R. (KBr): 3110, 2960, 1720, 1595, cm- 1 N.M.R 300 MHz (DMSO-d 6 8 10.4 111), 10.3 (bs, 1H), 9.2 1H), 7.1-6.5 (m, 41H1), 3.7-2.0 18H1), 1.8 3H), 1.0 12H).

MS (EI) m/z 437.3 EXAMPLE (±)-trans-2-Aminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoqainoline 3.24 g (10 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 6.16 g (30.0 mmol) of 2phenylhydrazono-3-oxobutyramide, 2.46 g (7.0 mmol) of CH 3 COONa, 7.85 g (120.0 mmol) of zinc dust and 15 ml of glacial acetic acid were treated as described in example 1. The residue was purified by chromatography on silica gel (Et 2 0- EtOAc/MeOH yielding 3.0 g of oily product which was triturated in Et 2

O

yielding 2.5 g of the title compound. M.p. 176-178 0

C

C

2 2

H

29

N

3 0 2 I.R. (neat): 3200, 2915, 2580, 1640, 1600, 1580 cm- 1 N.M.R. 300 MHz (DMSO-d6) 58 10.4 1H), 7.2-6.5 4H11), 3.8 3H), 3.0-1.8 18H), 1.0 3H).

MS (EI) mn/z 368.1 (Mi EXAMPLE 26 (±)-trans-2-Aminocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g) isoquinoline hydrochloride 0.48 g (1.3 immnol) of (±)-trans-2-aminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3methyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolol2,3-g) isoquinoline were treated with 0.75 ml (7.8 mmol) of boron tribromide as described in example 2. The crude product was purified by chromatography on silica gel (CH 2 Cl 2 /MeOH The residue was dissolved in MeOH and the solution brought to acidic pH with The solvent was evaporated in vacuo and the solid crystallized from acetone/MeOH, yielding 0.13 g of the title compound. M.p. 270-273 OC -31- I -e l- r~ r~ -ra~ -~l WO 95/04734 1ICT/10,04/021.2S C2 1 2 7

N

3 0 2 *HCl I.R. (KBr): 3160, 1645, 1595, 1450 cin1 N.M.R. 300 MHz (DMSO-d 6 8 10.5 1W), 10.2 (bs, 1W), 7.2-6.5 4H), 3.7-2.0 16H), 2.0 31I), 1.2 3H).

MS m/z 354.1 EXAMPLE 27 (±)-trans-6-Ethyl-2-ethoxycarbonyl-8a-(3-ethoxypheyl)-4,4a,5,6,7,8,8a,9octahydro-3-trifluromethyl- 1H-pyrrolo[2,3-g'isoquinoline 3.24 g (10 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoouinoline hydrochloride, 8.65 g (30 nmmol) of ethyl 2-phenylhydrazono-4,4,4-trifluoro-3-oxobutyrate, 2.46 g (30 inmol) of CH 3 C00Na, 7.85 g (120 Inmol) of zinc dust and 15 ml of glacial acetic acid were treated as described in example 1. The residue was purified by chromatography on silica gel (EtOAc/MeO 10%) yielding 3.0 g of product which was triturated in Et 2

O

yielding 2.5 g of the title compound. M.p. 209-211 'C 024 H 2 9

F

3

N

2 0 3 I.R. (neat): 3000, 1725, 1680, 1600 cm-1 N.M.R. 300 MHz (DMSO-d 6 (hydrochloride): 8 12.0 lW), 7.2-6.6 4H), 4.2 2H), 3.8 3W), 3.6-1.8 13H), 1.2 3H), 1.0 311).

MIS (ED) m/z 451.1 EXAMPLE 28 (±)-trans-6-Ethyl-2-ethoxycarbonyl-8a-(3-hydroxypheyl)-4,4a,5, 6 ,7, 8 8 a, 9 octahydro-3-trifluoroiethyl- 1H-pyrrolo[2,3-g]isoquinoline hydrochloride 0.6 g (1.3 miol) of (±)-trans-6-ethyl-2-ethoxycarbonyl-8a-(3-nethoxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro-3-trifluoroinethyl-lH-pyrrolo[2,3-g]isoquinoline were treated with 0.75 ml (7.8 mmol) of boron tribroiide as described in example 2. The crude product was purified by chromatography on silica gel (CH 2 C2/JMeOH 20%-4 The residue was dissolved in MeOH and the solution brought to acidic pH withl HCIIEt 2 O. The solvent was evaporated in vacuo and the solid was ttiturated in Et 2

O,

yielding 0. 14 g of the title compound. M.p. 275-27 8 'C

C

2 3

W

2 7

F

3

N

2 0 3

*HCI

1.R. (KBr): 3160, 2680, 1705, 1600, cm 1 N.M.R. 300 MHz (DMSO-d 6 8 12.1 1H), 10.4 (bs, 1H), 9.3 1W), 7.2-6.5 (m, 4H), 4.2 2H), 3.7-2.2 lOH), 2.0 3H), 1.2 6H).

MS (Elj m/z 436.1 -32e IPIIIPL~CI~-~ lm*a~ WO) 95/047344 W 3CT/,i014/0232 EXAMPLE 29 (h))trans-2-Diethylminocarbonyl-8a-(3-methoxyphenyl)-3-methyl-6-propyl- 4,4a,5,6,7,8,8a,9-octahycro- H-pyrrolot2,3-gisoquinoline hydrochloride 0.37 g (0.86 mnol) of (±)-trans-2-diethylaniinocarbonyl-8a-(3-methoxyphenyl)-3methyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoquinoline hydrochloride, 0.11 g (0.90 mnol) of propyl bromide, 0.24 g (1.71 mmol) of potassium carbonate and a catalytic amount of potassium iodide were dissolved in 5 ml of dimethylformamide and heated to 80 C for 2 h. The solvent was evaporated in vacuo, the residue was taken up in H 2 0 and extracted with EtOAc. The organic layer was separated, dried over Na 2 SO4 and the solvent removed in vacuo. The residue was dissolved in Et 2 O and the solution brought to acidic pH with HCI/Et 2 O. The precipitate was filtered yielding 0.25 g of the title compound. M.p, 102-106 IC dec.

C

2 7

H

3 9

N

3

O

2

-HCI

1.R. (KBr) 3400, 3200, 2915, 2580, 1715, 1600 cm- 1 EXAMPLE (±)-trans-2-Diethylarninocarbonyl-8a-(3-hydroxyphenyl)-3-methyl-6-propyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinoline hydrochloride 0.25 g (0.53 mmol) of (±)-trans-2-diethylaininocarbonyl-8a-(3-methoxyphenyl)-3methyl-6-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrTolo[ 2 3 -g isoquinoline hydrochloride were treated with 0.3 ml (3.18 nunvcl) of boron tribromide as described in example 2. The crude product was dissolved in MeOli and the solution brought to acidic pH with HCI/Et 2 O. The solvent was evaporated in vacuo and the solid crystallized from acetone, yielding 0.04 g of the title compound. M.p. 236-238 0

C.

C

2 6

H

3 7

N

3 0 2 -HCl I.R. 3130, 2915, 1590, 1460, cm- 1 N.M.R. 300 MHz (DMSO-d 6 8 10.2 9.0 1H), 7.2-6.4 4H), 3.7-2.2 12H), 2.0 3H), 1.8 2H), 1.6 2H), 1.0 6H), 0.8 6H) MS (El) n/z 423.2 EXAMPLE 31 (±)-trans-2-Dimethylaiinocarbonyl-6-ethyl-8a-(3-nethoxyphenyl)- 3 -methyl- 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g] isoquinoline g (3.1 imol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)--oxo- -33- ~eCI~LII*r~arr~a~-- l"l~~ WO 95/047341 WO CT/)14/0232S 1 ,2,3,4,4a,56,7,8,8a-deca ydroisoquinoline hydrochloride, 2,33 g (10 mmol) of N,Ndimethyl-2-phenylhydrazonv-3-oxobutyramide, 0.82 g (10 mmol) of CH 3 COONa, 2.6 g (40 mmol) of zinc dust arl 5 ml of glacial acctic acid were treated as described in example 1. The residue was purified by chromatography on silica gel (EtOAc/MeOH yielding 0.5 g of product which was crystallized from Et 2 O yielding 0.5 g of the title compound. M.p. 151-153 OC

C

2 4H 33

N

3 0 2 I.R. (neat) 3210, 2910, 1585 cm- 1 N.M.R 300 MHz (DMSO-d 6 (hydrochloride): 5 10.3 1H), 7.2-6.6 411), 3.8 311), 3.6-1.8 2211), 1.0 31) MS (EI) n/z 395.2 EXAMPLE 32 (±)-trans-2-Dimethylaminocaronyl-6-ethyl-8a-(3-hydroxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-gjisoquinoline hydrochloride g (1.25 imol) of (±)-trns-2-dimethylaninocarbonyl-6-ethyl-8a-(3rmethoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoquinoline were treated with 0.725 ml (7.5 mmol) of boron tribromide as described in example 2. The crude product was dissolved in MeOH and the solution brought to acidic pH with HCI/Et 2 O. The solvent was evaporated in vacuo and the solid crystallized from EtOH, yielding 0.15 g of the title compound. M.p. 305 *C dec.

C

23

H

3 1

N

3 0 2 .HCl I.R. (KBr): 3160, 1600, 1580 cm- N.M.R. 300 MHz (DMSO-d6): 5 10.4 1H), 10.2 (bs, 1H), 9.3 11), 7.2-6.5 (m, 4H), 3.7-2.0 2211), 1.2 311) MS (TSP) m/z 382.0 EXAMPLE 33 (-)-trans-2-iethylaminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a-octahydro- 1H-pyrrolo[12,3-giisoquinoline hydrochloride 1.9 g (5.87 mmnol) of (-)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloidi. (Int. Pat. AppI. WO 93/01186), 4.61 g (17.61 mmol) of N,N-diethyl-2-phenylhydrazono-3oxobutyramide, 1.45 g (17.61 mmol) of CH 3 COONa, 1.9 g (29.35 mmol) of zinc dust and 15 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography ((i-Pr) 2 0/MeO/conc. Ni 4 0H 75:25:0.5). The resulting solid was dissolved in acetone and the solution brought to -34- ~i pl~ 18""mrrrarrrmrr~-n~llll WO 95/04734C KIVU, 1194/0412 5,~2 acidic pI with HCI/-t 2 O, The solvent was evaporated in vacuo and the solid triturated witl Et20, yielding 2.3 g of the title compound, M.p. 201-205 'C.

C

2 6 1'1 37

N

3 02'1IC I.R, (K3r, 3400, 3200, 2920, 1600 cnAI N.M.R 300 MHz (DMSO-d6) 8 10.7 (bs, 1Hi), 10.4 11), 7.3-6.7 4H), 3.7 (s, 311), 3.6-2.5 171), 1.8 3H), 1.2-1.0 9H) fcaJ 20 D= -20.32 (c 1, MONl).

The I.R, and N.M.R, spectra were identical to those obtained for the racemate, EXAMPLE 34 (-)-trans-2-Diethylaminocarbonyl-6-ethyl-8a-(3-hydrocyphcnyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 111-pyrrolo[2,3-gisoquinoline hydrocWioride is 2.3 g (5.0 mmol) of (-)-trans 2-diethylaminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)- 3-mithyl-4,4a,5,6,7,8,8a-octahydro- 1H-pyrrolo[2,3-g]isoquinoline hydrochloride were treated with 2.9 ml (30 mmol) of boron tribronide as described in example 2.

The crude product was dissolved in MeOH and the solution brought to acidic pH with HCJIEt 2 O. The precipitate was filtered and crystallized from a mixture of acetone/MeOH 9/1, yielding 0,37g of the title compound. 239-241'C.

C

2 5

H

3 5

N

3 0 2 -HC1 I.R. (KBr) 3200, 2980, 2940, 1600 cm- N.M.R. 300 MHz (DMSO-d 6 5 10.4 111), 7.3-6.7 4H), 3.6-2.5 17H), 1.8 3H), 1.2-1.0 9H) MS (El) m/z 409.3 (ME).

[a] 20 D -57.94 (c 1, MeOH).

The I.R. and N.M.R. spectra were identical to those obtained for the racemate.

EXAMPLE (+)-trans-2-Diethylaminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a-octahydro- 1H-pyrrolo[2,3-glisoquinoline hydror'liioride 1.9 g (5.87 mnol) of (+)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1 ,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride (Int. Pat. Appi. WO 93/01186), 4.61 g (17.61 mmol) of N,N-diethyl-2-phenylhydrazono-3oxobutyraiide, 1.45 g (17.61 mmol) of CH 3 COONa, 1.9 g (29.35 mmnol) of zinc dust and 15 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography ((i-Pr) 2 0/MeQH/conc. NH 4 0H

I

~m~n*n umrr *rmirnrrar~-m~-r~-nrr-rJn~~l WO 95/047.34 11CO0,114="12.5asa, 75:25:0.5). The resulting solid wats dissolved in acetone and the solution brought to acidic p11 with iCl/E*t 2 O, The solvent was evaporated in vacuo and the solid triturated with Et 2 0, yielding 2.0 g of the title compound. Mp. 200-204 'C

C

26 F1 37

N

3 0 2

+ICI

(XIr) 3400, 3200, 2920, 1600 cn, N.M.R. 300 MHz (DM30-cl 6 5 107 (bs, 1W), 10.4 111), 7.3-6.7 4H), 3.7 (s, 311), 3.6-2,5 17H), 18 3H), 1.2-1.0 9H) D =+20.65 (e 1, MeO1).

io The LR. and N.M.R. spectra were identical to those obtained for the racemate.

EXAMPLE 36 (+-)-trans-2-Diethylaminocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3 .niethyl- 4,4a,5,6,7,8,8a,9-octahydro-H-pyrrolo[2,3-glfrquinoline hydrochloride g (4.3 mnmol) of (+)-trans-2-diethylaninocarbonyl-6-ethyl-8a-(3-netioxyphenyl)- 3-methyl-4,4a 1 5,6,7,8,8a-octahydro- 1H-pyrrolo[2,3-g]isoquinoline hydrochloride were treated with 2.5 ml (25.8 innol) of boron tribromide as described in example 2.

The crude product was dissolved in MeOH and the solution brought to acidic pH w.vith HCI/Et 2 O. The precipitate was filtered and crystallized from a mixture of acetone/MeOH 9/1, yielding 0.28 g of the title compound. M.p. 239-240 IC.

C

2 5

H

3 5

N

3 0 2

HCI

I.R. (KBr) 3200, 2980, 2940, 1600 cm- N.M.R. 300 MHz (DMSO-d 6 8 10.6 (bs, 11), 10.4 1H), 7.3-6.7 4H), 3.6- 2.5 17H), 1.8 311), 1.2-1.0 9H) MS (El) m/z 409.2 (1 20 D +57.49 (c 1, MeOW).

The I.R. and N.M.R. spectra were identical to those obtained for the racemate.

EXAMPLE 37 (±)-trans-2-Diethylaxinocarbonyl-6-(2furylmethyl)-8a-(3-iethoxyphenyl)-3methyl-4,4a,5,6,78 ,8a,9-octahydro- 1H-pyrrolo[2,3-g) isoquinoline hydrochloride 1.3 g (3.3 mmol) of (±)-trans-2-diethylaninocarbonyl-8a-(3-methoxyphenyl)-3iethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-gI isoquinoline, 0.28 ml (4.95 mmol) of acetic acid, 0.33 ml (3.96 imol) of 2-furaldehyde were dissolved in 50 ml of MeOH under nitrogen atmosphere. 0.415 g (6.6 imol) of sodium cyanoborohydride were added and the solution stirred for 15 h. Additional acetic acid -36i ,II- c Ul~ ~-pIraC l~ WO 95/0473I4 (0.1 m1), 2-furaldehyde (0.3 ml) and sodium cyanoborohydride (0.2 g) were added.

Aftem' two hours of stirring the reaction mixture was cooled to 0 OC and 50 ml of SN hydrochloric acid were added. The solvent was removed In vacuo, the aqueous solution was extracted with Et2O, the pH was adjusted to 8 with 20% NaOW and then extracted with AcOEt. The organic layer was dried over Na 2 SO4 and the solvent was removed in vacuo. The crude product was dissolved in acoione/McOH and the eolution brought to acidic pF1 with *-IC1Vit 2 0, The precipitate was filtercd, yielding 1.7 g of the tide compound. M.p. z 105 IC dec.

C

2 9 1-1 3 7

N

3 0 3

-CI

o I.R. (KBr): 3400, 3200, 2940,1600 cm- 1 N.M.R. 300 MFIz (DMSO-d6) 5 10.4 IN), 7.8-6.4 71-1), 4.2 211), 3,8 (s, 3.6-1.8 1811), 1.2-1.0 611) MS (El) r/z=475 EXAMPLE 38 (±)-trans-2-Diethylaminocarbonyl-6-(2-furymethyl)-8a-(3-hydroxyphenyl)-3methyl-4,4a,5,6,7,8,8a,9-octahydro- lH-pyrrolo[2,3-g) isoquinoline 1.7 g (3.32 mmol) of (±)-trans-2-dimethylaminiocarbonyl-6-(2-furylmethyl)-8a-(3methoxyphenyl)-3-iethyl-4,4a,5,6,7,8,8a,9-octahydro- IH-pyrrolo[2,3-gj isoquinoline hydrochloride were treated with 1.86 ml (19.9 mmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAcfMeONconc.NH40H 95:5:0.5). The solid was triturated with acetone, yielding 0.07 g of the title compound. M.p. 215-216 'C dec.

C

2 8

H

3 5

N

3 0 3 I.R. (KBr): 3340, 2930, 2900, 1590 cin' N.M.R. 300 MHz (DMSO-d6): 5 10.4 1H), 9.2 1H), 7.5 2H), 7.1-6.2 (m, 3.5-1.8 19H), 1.0 6H1).

MS (Er) mz 461.1 EXAMPLE 39 k s-2-thylaminocarbonyl-8a-( octahydro-I H-pyrrolo[2,3-g]isouinoline 1.6 g (5.7 mmol) of (±)-trans-4a-(3-methoxyphenyl)-6-oxo-1,2,3, 4 ,4a,5, 6 8 adecahydroisoquinoline hydrochloride, 6.0 g (22.8 mol) of N,N-diethyl-2phenylhydr-azono-3-oxobutyrarrde, 1.9 g (22.8 mmol) of CH 3 COONa, 2.2 g (34.2 mnnol),of zinc dust and 30 ml of glacial Icetic acid were treated as described in example 1, yielding 1.3 g of the title compound. M.p. 197-199 'C.

-37- IIBr( -a"D-U"3~IC WO 9/04734 CTA0/41.

C

24 14 33

N

3 0 2 I.R, 3270,2915, 1605 cm- EXAMPLE (±)trans-6.lutyl-2dlethylaninocarbo nyl-8a-(3-nthoxypony)-3-mthyl- 4,4;tS 8,8a-octaydro- 11-pyrrolo[2,3-giisoquihiolinc 0.2 g (0,57 wnol) of (dL).trans-2-buty1-4a-(3-metioxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7 ,$,8a.deeaiydroisoqtuinroline hydrochloride, 0.45 g (1.71 mmol) of NN-dietliy!-2-phnylhly&azono3-oobutyramide, 0.14 g (1.71 mnol) of CfX 3 COONa, 0.22 g (3.42 mmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1, yielding 0,15 g of the title compound. Mp. =134 IC dec.

C

2 8

H

41

N

3 0 2 1s L.R, (hydrochloride): 3200, 2960, 2925, 1630, 1600 coy 1 EXAMPLE 41 )-trans-6-13utyl-2-diethylaminocarbonyl-8a-(3-hydroxyphenyl)-3-mthyl- 4,4a,5,6,7,8,8a-octahydro- 1H-pyrrolof2,3-gisoquinoline 0.15 g (0.31 mmol) of (±)-tran s-6-butyl-2-diethylaniinocarbonyl-8a.(3methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a-octahy&o- lH-pyrrolo[2,3-glisoquinoline were treated with 0.174 ml (1.86 mnmol) of boron tribromide as described in example 2, yielding 0.06 g of the title compound. M.p. 228-229 C

C

2 7

H

3 9

N

3 0 2 I.R. (KBr): 3330, 2920, 1590 cm- 1 EXAMPLE 42 (±)-traxs-7-Ethyl-4a-(3-methoxyphenyl)- 1 -methyl-4,4a,5,6,7,8,8a,9-octahydro-2phenyl-l 1,-imidazo[4,5-glisoquinoline A solution of 0.46 g (2.98 mmol) of N-methylbenzimidoyl chloride Am. Chem, Soc., 1962, 84, 7L in 12 mrl of THJ2F w'as cooled to -78 'C under nitrogen atmosphere and 0.73 ml (5.21 mmol) of triethylamine were added, After 30 min a solution of 0.45 g (1.49 mmol) of (±)-trans-2-ethyl-6-hydroxyimino0-4a-(3methoxyphenyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline in 3 ml of THF was added. The reaction mixture was allowed to warm to room temperature and then refluxed for 5 h. Water was added and the mixture was extracted with CH 2 1 2 The organic layer was washed with brine and dried. The solvent was removed in vacuc -38- WO 951047341 B'Cr'l~tliw~15262~~aS and the resulting product was dissolved in 25 il of toluene, 0.99 g of ptoluenesulphonic acid w re added and the reaction mixture was heated to reflux in a Dean-Stark apparatus foa 0' Th. solvent was removed in vacuo, the residue was taken up in water, the pH 1 djusted to 10 with IN NaOH. The aqueous layer was extracted with CH 2 Cl 2 the organic layer was dried and the solvent was removed in vacuo. The cude product was purified by flash chromatography (EtOAc/MeOH/conc.NH 4 OH 85:15:2) yielding 0.276 g of the title compound. M.p. 146-150 0

C.

C

2

MH

3 1 N0 R. R(KBr): 3920, 1600, 1580 cm-1 N.M.LR. 300 M.Hz (DMSO-d 6 8 7.6-6.6 9H), 3.8 3H3), 3.5 3H), 3.0-1.6 (n, 13H), 1.0 3H).

MS (EI) m/z 401.2 EXAMPLE 43 (±)-trans-7-kth'yl-4a-(3-hydroxyphenyl)- l-methyl-4,4a,5,6, 7,8,8a,9-octahydro-2phenyl-l H-imidazo[4,5-g isoquinoline 0.27 g (0.67 mmol) of (±)-trans-7-ethyl-4a-(3-methoxyphenyl)- 1-methyl- 4,4a,5,6,7,8,8a,9-octahydro-2-p'Pnyl-lH-imidazo[4,5-g]isoquinoline were treated with 0.38 ml (4.02 rnniol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAc/MeOHlconcNH 4 OH 80:20:2). The resulting solid was crystallized from acetone, yielding 0.13 g of the title compound.

M.p. 249-251 *C.

C

25

H

2 9

N

3 0 I.R. (KBr): 3400, 2940, 1595, 1450 cm- 1 N.M.R. 300 MHz (DMSO-d 6 8 9.1 1H), 7.8-6.4 9H), 3.5 3H), 3.0-1.6 (n, 13H), 0 3H).

MS (El) m/z 387.2 EXAMPLE 44 (±)-trans-6-Ethyl-8a-(3-methoxyphenyl)-3-methyl-2-pyrrolidinocarbonyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyri'olo[2,3-g isoquinoline hydrochloride 1 g (3.1 minol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoqunoline hydrochloride, 2.4 g (9.3 inmol) of 1-(2phenylhydrazc.,io-3-oxobuyryl)pyrrolidine, 0.76 g (9.3 mnol) of CH 3 COONa, 2.4 g (37.2 rnmol) of zinc dust and 10 ml of glacial acetic acid were treated as described in example 1. The crude product was purified by flash chromatography -39e-~s~r~-l~q~lp III~ WO 95/04134 WO 9S/04134 INN/02S (EtOAc/MeQWconc.NH4OH 80:20:0.5). The residue was dissolved in acetone and the solurOn bronght to acidic pH with HCI/Et 2 Q. The precipitate was filtered, yieldhr-i (j,63 g of the title compound. M~p, 127-13 1 'C.

C

2 6

H

3 5

N

3

O

2

-HCI

I.R. 3280, 2940, 1610, 1580 cm EX.AM'PLE (±)-trans-6-Ethyl-8a-(3-hydroxyphenyl)-3-methyl-2-pyrrolidinocarbonyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinoline 0.63 g (1.37 mmol) of (±)-trans-6-ethyl-8a-(3-methoxyphenyl)-3-methyl-2pyrrolidinocarbonyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-glisoquinoline were treated with 0.77 ml (8.22 rnmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAcIMeOH/conc.NH 4

OH

80:20:0.5). The resulting solid was triturated with Et 2 O, yielding 0. 13 g of the title compound. M.p. 224-226 *C.

C

2 5

H

3 3

N

3 0 2 I.R. (KBr): 3400, 2940, 1595, 1450 cm- EXAMPLE 46 (±)-trans-2-Diisopropylaminocarbonyl-8a-(3-methoxyphenyl)-3-methyl-6-propyl- 4,4a,5,6,7,8,8a-octahydro- IH-pyrrolo[2,3-glisoquinoline hydrochloride 0.34 g (0.74 mrnol) of (±)-trans-2-diisopropylaminocarbonyl-8a-(3-methoxyphenyl)- 3-methyl-4,4a,5,6,7,8,8a,9-octahydro 1H-pyrrolo[2,3-g] isoquinoline hydrochloride, 0.095 g (0.78 mmol) of propyl bromide, 0.204 g (1.48 mmol) of potassium carbonate and a catalytic amount of potassium iodide in 5 ml of dimethylformamide were treated as described in example 29. The residue was dissolved in Et 2 O and the solution brought to acidic pH with HCl/Et 2 O. The prvecipitate was filtered yielding 0.22 g of the title compound. M.p. 150 'C dec.

C

29

H

4 3

N

3 0 2

-HCI

I.R. (KBr) 3400, 3200, 2915, 2580, 1600 cm- I EXAMPLE 47 (±)-tras-2-Diisopropylaminocarbonyl-8a-(3-hydroxyphelyl)-3-methyl-6-propylk 4,4a,5,6,7,8,8a-octahydro- 1H-pyrrolo[2,3-glisoquinoline hydrochloride 0.22 g (0.44 mniol) of (±)-trans-2-diisopropylaminocarbonyl-8a-(3-methoxyphenyl)- 3-ehl6poy-,a567'8-cayr-Hproo23giounln WO 95/047.14 hydrochloride were treated with 0.25 ml (2.64 minol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAcfMeOH/conc.NHi4Q1- 80:20:0.5). The residue was dissolved in acetone and the solution brought to acidic pH with HCI/E 2 O. The precipitate was filtered.

yielding 0.055 g of the title compound. M.p. =240-243 TC.

C

28

H

4 1

N

3

O

2 -HCl LR. (KBr): 3400, 2940, 1595,1450 cm- 1 -41 A~mmiAICPrrrsruPaaarsr~-rr~sr~ WO6 95/047341 WO'rrlfV9 /XC 4 /0 232.

CHEMXCAL TABLrE Ex.n. R RI R2 R3 R4 R5 j Molecular formula M.P. *C 1 Et m-OMe H H CONEt2 Me C 2 6H 3 7 N30 2 247 dec.

(as HC1) Rs 2 Et r-OH H H CONEt2 Me t:C/ 4 C 25

H

3 5 N30 2 221-223 3 Et m-OMe H H COOEC Me W C24H 32 N203

R

4 Etl r-OH H H COOEL Me -P 4 H 3

ON

2 03 0.5 1120 195-197

R

5 Et m-OMe H H CON-n-Pr 2 Me C 2 8J4N302HC 250 dec.

6 Et m-OH H H CON-n-Pr 2 Me C 27

H

3 9 N30 2 151-153 7 Et r-OMe H H COO-i-Bu Me C 2 6

H

3 6

N

2 0 3 HC1 230 dec.

H 8 Et m-OH H H COOi-Bu Me C 25 HMN2O3 196-198 9 Me m-OMe H H CONEt2 Me R4) C 2 5

H

35 N302 250 dec.

(as -HCI) Me m-Oh H H CONI2 Me C 24

H

3 3N3O2lCl >250 -42- SUBSTITUTE SHEET (RULE 26) I -1 7 I WO 95/04734 PCWHOM/02,M CMICAL, TABLE (continued)

P-

RR

I CONEt2 Me I± C8 CONt 2 P Me I± CL/1

CONHCH

2 Ph Me N 4 0C- RS

CQN(-CH

2 4 Me4(±

R

ICON(-CH

2 me NH W C2, ICONHPh me ICSNBth Me C

R

5 -43 SUBSTITUTE SHEET (RULE 26) WO 95/04734 PCT'1/89) 4/02325 CHEMICAL TABLE (continued) 1 ct

I

-44- SUBSTITUTE SHEET (RULE 26) I I p- -~IP-I ~BQ~eW~W~lil~aar~nnvplr r WO 95/04734 CHEMICAL TABLE (continued) R;j ~a- )n R3

F

I

3 R R R )n Molec CONMe2 Me C24

R

CONMe2 Me C23H.

R

SCONEt 2 Me C26H~ CONEt 2 Me C2 I

R

CONEt 2 Me C2H3 CONEt Me C25Ht3

R

CONEt2 Me C29H3

R

CONEt 2 Me C243 CONEt2l Me' [yi C 2 H3~ CONEt 2 Me 11t C281

R

5 CON~t 2 me, ,W C4 CON i Me _1 -R4 C 281 45 SUBSTITUTE SHEET (RULE 26) i rC WO 98104134 PffPOT/1204/IO2 CHEMICAL TAfLE (coninued) E.l R I R2R3 R4 R5 1 jMolecular formula M..

0

C

41 n-Bu m-OH H H CON~t 2 Me W) C27H39N3430 228-229 I/ 4 42 Et m-OMe H H Ph Me W C26H31N30 146-150 43 Et m-OH H H Ph Me C25H29N30 249-251 44 Et rn-OMe H H CON(-CH 2 4 Me C26H35N3O2HCI 127-131 Et r-OH 'H H CON(-CH 2 4 Me C2533N3O 2 224-226 46 n-Pr rn-OWe H H CON(i-Pr)2 Me C29H43N3O-Ha 150 dec.

47 n-Pr m-OH H H CON(i-Pr)2 Me W C28H41N3O2-HCI 240-243

R

-46- SUBSTITUTE SHEET (RULE 26)

II,

WO 90) 04734 WV3T/'94(/2328{ PHARMACOLOGICAL METHODS AND RESULTS OPIOID RADIOLIGAND BINDING ASSAYS Mouse brain membranes were prepared as described by Kosterlitz (Br. J. Pharmacol., 1981, 939.). The binding of the preferential delta ligand 3 H]-[D-Ala 2 ,D-Leu 5 enkephalin (DADLE) was evaluated at its KD concentration (1.3 nM) in presence of nM of the unlabelled mu ligand (D-Ala 2 MePhe 4 (DAMGO). The binding of the mu ligand 3 H-DAMGO (Eur. J. Pharmacol., 1989, .16, 213) and of the kappa ligand 3 H]-U69593 (Excerpta Medica, 1990,211) were carried out at 0.5 nM. The non-specific binding was determined in presence of naloxone (10 gpM) for all tritiated ligands. Binding data were expressed as percentage of inhibition and fitted the following equation: f(x) 100-X/(IC 5 0 X) where X are cold drug concentration values. The IC50 obtained were used to calculate the inhibitory constants (Ki) accordingly to the Cheng and Prusoff relation (Biochem.

Pharmacol., 1973,22, 3099).

MOUSE VAS DEFERENS (MVD) BIOASSAYS Vasa deferentia were obtained from CD-1 mice and were suspended in a Mg 2 +-free Krebs buffer at 37 For the delta agonist/antagonist studies, the tissues were electrically stimulated with pulse trains having the following parameters: train duration 50 ms, stimulus duration 2 ms, frequency of stimuli 50 Hz, maximal voltage 60-70 V, train frequency 0.1 Hz. Concentration response curves for each compounds were constructed cumulatively. Linear regression analysis and IC50 concentrations were evaluated according to Tallarida and Murray (Manual of Pharmacological Calculations, Springer Verlag NY, 1981).

The most potent compounds described in the present invention showed affinities for the delta receptor ranging from 0.5 to 200 nM with delta selectivity ranging from to 1500 times in respect to the other opioid receptor types. These compounds displayed also potent delta agonist and antagonist properties in the MVD preparation.

Selective delta agonists (antagonised by the selective delta antagonist naltrindole) displayed IC50s ranging from 1 to 500 nM. For example, compound of example 34 shows a Ki delta 0.73 nM, Ki mu/Ki delta 110 and Ki kappa/Ki delta 1105 and an IC 5 0 26 nM in the MVD preparation.

Selective delta antagonists showed Kes against DADLE ranging from 1 to 50 nM.

For example, compound of example 10 shows a Ki delta 2.15 nM, Ki mu/Ki delta and Ki kappa/Ki delta 403 and a Ke 7 nM against DADLE in the MVD preparation.

Mouse abdominal constriction (MAC) (Proc. Soc. Exp. Biol. Med., 1957, 95, 729), -47p WO 9~5/0434 !CT/I7W4/0232 mouse tail-flick (MTF) (J Pharm. Exp. Ther., 1941, 2, 74) and mouse tal-flick warm water (MTF-WW) (Life Sci., 1986, 1795) were adopted to evaluate the antinociceptive efficacy of the compounds of the present invention, Throughout this specification and the claims which follow, unless the context requires otherwise, ithe word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

a a e0 95 Sea.

5.9.

9* *9 e o

S

-48

Claims (3)

1. A compound, or solvate or salt thereof, of formula R 2 N3I) wherein: R is hydrogen or a straight or branched C I-C 5 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 6 cycloalkylalkyl, C 3 -C 5 alkenyl, aryl, aralkyl or furan-2-yl-alkyl; RI and R 2 which can be the aame or different, are each hydrogen, hydroxy, C I-C 3 alkoxy, halogen, SH, Cl-C 4 -alcylthio, NH6 NR 6 R 7 NHCOR 6 NHS0 2 R 6 wherein R 6 and R 7 which are the same or different, are hydrogen or C 1 -C 6 alkyl; R 3 is hydrogen, hydroxy or C I-C 3 alkoxy; R4 isa group (RI and R 2 having the meanings defined above) or a -C(Z)-R 8 group, in which Z is oxygen or sulphur, and R 8 is Cl-C 1

8-alkyl, Cl.-C 1 8 -alkoxy or NR 9 RI 0 wherein R 9 and RIO, which may be the same or different, are hydrogen, straight or branched C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C6 cycloalkylalkyl, C 3 -C 6 alkenyl, aryl, aralkyl oraOYLMD -sorn or, taken together with the nitrogen atom which they arelinked to,-they form an alkylene chain having from 2 to 5 carbon atoms, optionally interrupted by an oxygen or nitrogen atom; or R4is agroup R 11 -N-CZ-R 12 in which R 1 1 and R 12 are the same as R 9 and R 10 respectively, and Z is as defined above; R 5 is hydrogen, ClPC18 alkyl, C 2 -C 18 alkenyl, trifluoromethyl or is a -49- WO 95/04734 group (R I and R 2 having the meanings defined above); n is zero or 1; if n is zero, one of X or Y is NH, oxygen or sulphur, and the other is NH, CH or a R 4 or R5-substituted carbon atom; if n is 1, then X and Y are both nitrogen, or one of them is nitrogen and the other is CH or a R-or R 5 -substitu ted carbon atom. 2. A compound according to claim 1 in which R is methyl, ethyl, Scyclopropylrnethyl, propyl, 2-phenylethyl or 2-furylmethyl. 3. A compound according to claim I or 2 in which each of R I and R 2 is hydrogen, hydroxy, methoxy, chlorine, bromine, fluorine, SH, methylthio, amino, methylamino, ethylan-ino, dimethylamino, diethylamino, diisopropylamino, methylisopropylanino, acetylamino or sulfonylaniino, at any position of the ring. 4. A compound according to any one of claims 1 to 3 in which R 5 is hydrogen, methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, dodecyl, octadecyl, ally!. trifluoromethyl or phenyl. 2o 5. A compound according to any one of claims 1 to 4 in which R 4 is ethoxycarbonyl, i-butyloxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, pyrrolidinocarbonyl, benzylaminocarbonyl, phenylaminocarbonyl, morpholinocarbonyl, N-ethyl-N-i-isopropylaminocarbonyl, diethylaminothiocarbonyl, or phenyl. 6. A compound selected from: (±)-trans-2-Diethylaininocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a-octahydro- 1H-pyrrolo[2,3-g]isoquinoline; (±)-trans-2-Diethylaminocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinoline; (±)-trans-6-Ethyl-2-ethoxycarbonyl-3-methyl-8a-(3-methoxyphenyl)- WO 9SI047134 VCT/10" 41/0132 4,4a,5,6,7,8,8a,9-octahydro- 11 Wpyrrolo2,3g~isoqirioline,, (±)-transq-6-Ethyl-2-ethoxycarbonyl- 8a..(3-hydroxyphienyl)-3-methyl- 4,4a,5,6,7,8,ga,9-octahydro- lH.pyrrolo[2,3-gjisoquinoline;, (±)-trans-Dipropylaminocarboiyl-6-ethy-3-methy-8a-(3-methoxyphelyl)- 4,4a,5 ,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g~isoquinoline hydrochloride; (±)-trans-Dipropylaminocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3-methylb 4,4a,5,6,7,8,8a,9-octahydro- IH-pyrrolo[2,3-g]isoquinoline; (±)-trans-2-(i-Butoxycarbonyl)-6-ethyl-3-nethy1-8a-(3-methoxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-gjisoquinoline hydrochloride; (±)-trans-2-(i-Butoxycarbonyl)-6-ethyl-8a-(3-hydroxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro-IH-pyrrolo[2,3-g]isoquinoline hydrochloride; (±)-trans-2-Diethylaminocatrbonyl-3,6-dimethyl-8a-(3-methoxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinoline; (±)-trans-2-Dietylaxninocarbonyl-3,6-dimethyl-8a-(3-hydroxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-glisoquinoline hydrochloride; (±)-trans-2-Diethylaniinocarbnyl-3,7-dimethyl-4a-(3-methoxypheflyl)- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[3,2-g]isoquinoline; (±)-trans-2-Diethylaminocarbonyl-3,7-dimethyl-4a-(3-hydroxyphelyl)- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrololl3,2-g]isoquinoline; (±).tras-2-Benzylaminocarbon-yi-3,6-ciimethy-8a-(3-methoxypheflyl)- 4,4a,5,6,7,8,8a,9-octahydro- I--pyrrololl2,3-g]isoquinoline; (±)-trans-2-Benzylaminocarbonyl-3,6-dimethyl-8a-(3hydroxypheflyl) 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinolifle hydrochloride; (±-rn-,-iehl8-3mtoxpey)2proiioabnl 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinolifle; (±-ris36Dmty-a(-yrxpey)2proiioabnl -51- 4,4a,5,6,7,8,8a,9-octahiydro- l-pyrolot2,3-bg~i.oquiiioline hydrochloride; (±)-trans-6-Pthyl3-metyl-8a-(3-ethoxyphefyl)2-phnylamiocrbonl-l 4,4a,5,6,7,8,8a,9-octahydro- Hl-pyrrolo[2,3-g)isoquinoline; (±)-trans-6-Ethyl-8a-(3-hydroxyphenyl)-3-methyl-2-phenylaminocarbonyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-gliisoquinoline; (±)-tras-2-Diethylxninothiocarbonyl-6-ethyl-3-methyl-8a-(3-methoxyphenyl)- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-gljisoquinoline; (±)-trans-2-Diethylaminothiocarbonyl-6-ethyl-8a-(3-hydroxyphenyl)-3-niethyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g]isoquinoline; (±)-traris-6-Cyclopropylmethyl-2-diethylaminocarbonyl-8a-(3-methoxyphenyl)-3- methyl-4,4a,5,6,7,8,8a,9-octahydro- IH-pyrrolo[2,3-g] isoquinoline hydrochloride; (±)-trans-6-Cyclopropylmethyl-2-diethylaninocarbonyl-8a-(3-hydroxyphenyl)-3- methyl-4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoquinoline hydrochloride; (±)-trans-2-Diisopropylaminocarbonyl-6-ethyl-8a-(3-methoxyphienyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrroloU',,3-g] isoquinoline; (±)-trans-2-Diisopropylaminocarbonyl-6-ethyl-8a-(3-hydroxyphelyl)-3-mlethyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-glisoquinoline hydrochloride; (±)-tans-2-Axninocarbonyl-6-ethyl-8a-(3-nhethoxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-g] isoquinoline; (±t)-trans-2-Aminiocarbonyl-6-ethyl-8a-(3-hydroxyphelyl)-3-mlethyl- 4,4a,5,6,7,8,8a,9-octahydro-H-pyrrolo[2,3-gI isoquinoline hydrochloride; (±-rn--ty--toyabnl8-(-ehxpey)44,,,,,a9 octahydr&.-3-trifluoromethyl- 1H-pyrrolo[2,3-g]isoquinoline; (±-rn--ty--toyabnl8-(-yrxpey)44,,,,,a9 ocaym3tfumPty-Hproo23giounln hydrochloride; (±-rn--ityaioabnl8-(-ehxpey)3mty--rpl 52 WO) 9S104134 PCTx/18i114I2325 4,4a,5,6,7,8,a,9-octahydr-iilpyrro1o[2,3gisoquilolifle hydrochloride; (Lf)-trans-2-Diethylaninocarbonyl-8a-(3-hydroxcyphenyl)-3-methyl-6-propyl- 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-gjisoquinolifl: hydrochloride; (*t)-rans-2-Dimethylaninocabonyl-6-ethyl-8a-(3-methoxyphenl)-3-methyl- 4.4a,5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-gI isoquirioline; (±)Arans-2-Dimethylanmiocarbonyl-6-ethiyl-8a-(3-hydroxyphenyl)-3-rnethyl- 4,4a,5,6,7,8,8a,9-ortahy 2am lIHpyrrolo[2,3-g]isoquinoliiije hydrochloride; (-)-trans-2-Diethylaminocabonyl-6-ethiyl-8a-(3-methoxyph .yi)-3-methyl- 4,4a,5,6,7,8,8a-octahydro-1H-pyrroloI2,3-glisoquinoline ]hydrochloride; (-)-trans-2-Diethylaminocarbanyl-6-ethyl-8a-(3-hydroxyphenyl)-3-rnethyl- 4,4-t,5,6,7,8,8a,9-octahydro- lH-pyrrolo[2,3-glisoquinoline hydrochloride; (+)-trans-2-Diethylaminocarbony1-6§-ethy-8a-(3-methoxyphenyl)-3-methyl- 4,4a,5,6,7,8,8a-octahydro- 1fl-pyrrolo[2,3-glisoquinoline hydrochloride; (+)-tr-ans-2-Diethylaniinocairbonyl-6-ethy[-8a-(3-hydroxyphenyl)-3-mfethyl- 4,4a,5,6,7,8,8a,9-octahydwo-I1H-pyrrolo[2,3-gjisoquinoline hydrochloride;, (±)-trns-2-Diehylamintirbony~l.6-(2-furylmethyl)-8a-(3-methoyphelyl)-3- methyI-4,4a 1 5,6,7,8,8a,9-octahydro- 1H-pyrrolo[2,3-gI isoquinoline hydrochloride; (±-rn--ityr',.Jabnl6(2frlehl-a(-yrxpey)3 methyl-4,4a,5,6,7,8,8$,9-octahydro-H-pyrTolo[2,3-g] isoquinoline; (±)-trans-2-Diethylaninocarbonyl-8a-(3-methoxypheflyl)-3-methyl-4, 4 a,, 6 7 8 8 a- ociahydro- 1H-pyrrolo[2,3-glisoquinoline; (±-rn--uy--ityaioabnl8-3mtoyhnl--ehl 4,4a,5,6,7,8,8a-octahydro-lH-pyrrolo[2,3-gisoquilolile; (±-rn--uy--~ehlmncronl8.3hdoyhnl-2-ehl 4,4a,5,6,7,8,8a-octaiydro-lH-pyrrolo[2,3gisoquiflolile; (±)-trans-7-Ethyl41-(3-methoxyphenlyl)-l1-methyl-4,4a,5,6,7,8,8a,9-octahydrco-2- 53 I'rlU1'II(C\I~Uf\V14Y3r~WeWI ,(/llrllY't -54. phenyl- i (±)-ti~s-7-Etlhyl-4a-(3-hiydroxyphcny)I -medhyl-4,4a, 5,6,7,8,8a, 9-octahydro-2-phenyt-1 11- isoqu inot ine; s-6-E-me1,4a,5 8a, 9- octahtydro- 1I -pyrrolo[2,3-glisoquinolite hydrochloride; (±)-trans-6-Etlyl-8a-(3 -hydroxyphenyl)-3-methyl-2-pyrro] id i nocarbonyl-4,4a, 5,6,7,8,8a- octahyclro-l H-pyrrolo[2,3-gjisoquitoline; (±)-trainis-2Diisopropyainocarbo y8a-(3-mletioxyphcUyl)-3-ilt1y1 -6-propyl- 4, 4a,5 ,6,7,8,8a-octaiyd ro- I-I-pyrrolo[2,3-g3isoquinolinc hydrochloride; and (±)-trans-2-Diisopropylaininocarbonyl-8a-(3-hydroxy'pheyl)-3-methy1-6-propyl- i S 4,4a,5,6,7,8, 8a-octahiydro-iH-pyrrolo(2,3-g isoquinoline -hydrochloride. 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 8. A method for achieving an immunomodulatory or cardiovascular effect comprising administering to a mammal in need thereof a compound according to any one of claims I to 6.

9. A method for the manufacture of a medicament for the treatment of pain or as an immunomodulating and/or cardiovascular agent comprising the step of bringing a compound according to any one of claims 1 to 6 into a form suitable for administration. A method for the treatment and/or prophylaxis of pain and of rejection of transplants .,,and skin grafts in mammals particularly humans, which comprises administering to the -I I, mammal in need of such trevtment and/or prophylaxis an effective amount of a compound according to any one of claims 1 to 6. 11, Thle compounds of any one of claims I. to 6, compositions of claim 7 or methods of claims 8 to 10, substantially as hereinbefore described with reference to the Examples. DATED this FOURTEENTHT day of OCTOB3ER 1997 Sinithlfine Beeclian SpA B3y DAVIES COLLISON CAVE 1 0 Patent Attorneys for the applicant 4o *og INIT NAT4IONAL SEARCH IPORT WWMT/ I Ai,401 No ACIASSIPICATIONOFSUEI ATR ,PC 6 C070471/04 AG 1K3 1/435 C07D498/04 C070491./048 C07DS13/04 C070495/04 //(CO7D471/04,221:-00,209:00), (C070471/04,235.-00, 221:00) According to International Patent Cisarification (IPC or to both national classification and IPC 13 IIELDS SIIARCHGO3 Minimum documentation searched (classification system followed by classificAtion symbols) IPC 6 C07D A61K Documentation searced other than minimum documentation to the extent that such documents Are included in the fields searched Electronic dlaa base consulted during the international search (name of data base and, whcre practical, search terms used) C. DOCUMENTS CONSIDERED TO BE1 RELEVANT________ Category' Citation of document 1 with indication, where Appropriate, of the relevant pastsgcs Relevant to claim No. A WO,A,93 01186 (ZAMBELETTI) 21 January 1,10 1993 cited in the application see page 1, line 26 -line 29; claims 1,11 Pl urther documents are listed in the contiation of box C. MV Patent family members are listed in anex. *Special categories of cited doctuments 'r lae document published after the international filing date *A dcumnt efiingthegeneal tat oftheartwhic Isnotor r~oitydate and not in conflict with the application but W dcneto ef pticl eleacfte cite whic unnoderstand the principle or theory underlying the consdere tobe o paticuar clevnceinvention VII earlier document but published on or after the international 'X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to Vj document which may throw doubts on priority dialn~s) or involve An inventive step when the document is taken alone which is cited to establish the publication date of another *Y document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the '0 document rcferting to an oral disclosuire, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled V~ document published prior to the international filing date but in the art later thant the priority date claimed W' document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report November 1994 21. 11. 94f Name and mailing addresofthe ISA Authorized officer European Patent Office, P.13. 58IS Patentlaan 2 NL 2280 1IV Riliwik Tel. 3171)34042040, Tx. 31 651 epo nl, Afr as Pam 31.70) 340-3016 Afr as F~orm PCT/IMA/210 (mcad sOwn) (July 1992) INURltNATIONAL SClARC111 A (IIKtOflAl OPll1tI0h No. PCT/ LIP 94/ 02.325 Box I ObwenvAtiona whcro~ ertainr claims wero round unscarclhablo (Continuation of Item I of flrst 14heet) ThiInterational search report has not been established it) respect of corta claims under Article 17(2)(a) for thn following rcasonls 1. Cialms Nos.: because they relate to sub)=c matter not required to be starched by ths Authority, narnely. Although claim 13. is directed to a method of treatment of (diagnostic method practised on) the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. FL1 ClaimsNs: because they relate to parts or the international application that do not comply with the prescribed requirements to such an extent that no meaniunternational mearch can be carried out, specifically: 3. Claim# Nos.: -bemause they are dependent claims and arm not drafted In accordance with the second and third sentence& of Rule 6.4(z). Biox 11 Observations where unity of Invention Is lacking (continuation or item 2 of first sheet) This International searching Authority found multiple inventions In this International application, as follows:, 1. ElAs all required additional search fees were timely paid by thle applicant, thO International search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying in additional fee, this Authority did not invite payment of any addtional fee. 3. []As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, spcifically chlms No..; 4. F No required adtonal search fees were timely paid by the applicant. Consequently, -this International search report is restricted to the Invention first mentioned In the claimrs; It is covered by claims Nos.: Remark on Pretext ElThe addtional search fees were accompanied by the applicnt' protest. DNo protest accompaniled the payment of additional search fees. Form PC/ISA/210 (continuation of first sheet (July 1992) P~t4~IA~n~y ~PCT/EP 94/09396 Patent document Publlk on Patent family PUbIlcAtlon cited In search report ditto rnomber(ii)I WO-A-9301186 21-01-93 AU-A- 2194892 11-02-93 EP-A- 0596897 18-05-94 Foim pCTIWIO (patwt tmily anrwz) (July 1992)